#2021SBR-JUL/Q01
#2021SBR-JUL/Q03
#2021SBR-JUL/Q13
#2021SBR-JUL/Q13

Right Bundle branch block

Over days to weeks the brain tissue compensates for reduced extracellular tonicity by extruding solutes.
#2021SBR-JUL/Q15

• If even even mild symptoms are present, 100ml bolus of 3% NaCl is given and repeated as needed (maximum 3 boluses) to raise Na by 4-6 mEq / L in the first few hours hour.

Risk factors for ODS:
Patients with hypokalemia, female gender, or history of alcoholism or liver transplant, Na < 105, malnourishment, concurrent liver disease.

Treatment is based on the level of hyponatremia:

1. Mild (Na > 130) - no need to 3% NaCl)
2. Moderate to severe (Na < 130)
   1. Severe symptoms - 3% NaCl 100 ml bolus
   2. Mild to moderate symptoms
      1. 120 - 129 - no need for hypertonic saline

| 2 points | Age ≥75 years |
| 2 points | Stroke/Transient Ischemic Attack/Thromboembolic event |

[!INFO] Definition of DKA

pH can be normal while still statisfying criteria for DKA.

• Two proposed reasons for observing lower glucose levels in DKA
  • Patients with DKA present earlier with symptoms. Symptoms of hyperosmolarity tend to present later. (so there's more time for hyperglycemia to develop)
  • Patients with DKA are younger and usually present early in the development of Diabetes. Young patients, and those with early diabetes have elevated GFR. Therefore, DKA patients usually have high GFR which causes a lot of glucose to be lost via the urine -> this limits serum glucose concentration.

Management of DKA And HSS

#2021SBR-JUL/Q14

[!INFO]
For DKA, expected target is resolution of ketonaemia and acidosis in 24 hours.

Replace total fluid deficit in 24 hours

Initial hour

- Second liter of fluid usually requires potassium addion. See [[#Electrolytes]] below.

60 minutes to 6 hours

• Target a rate of fall of ketons of 0.5 mmol/L/hr or rise of HCO3 of 3mmol/L/hr.
• Blood glucose fall of 3mmol / L / hr (54 mg/dL / Hr)
• If blood flucose falls below 14mmol/L (252 mg/Ld) add 10% dextrose 125 ml/hr.
  Patients have a total potassium deficit (due to vomiting and diuresis) but it is masked by shift of KCl from ICF to ECF. Insulin administration will unmask the deficit and cause rapid fall of serum K+ as K+ shifts back into cells.
• The addition of K+ is likely required with the second litre of fluid.
• Potassium replacement doses:
  • 
  • Start potassium infusion even when K+ level is within normal

When to titrate dose:

• If not meeting the targets [[#60 minutes to 6 hours|above]] above for rate of resolution
• Can reduce dose to 0.05u/Kg/hr in patient becomes hypoglycaemic.

When to stop:
Until ketones < 0.6 mmol/L OR venous pH > 7.3 OR venous bicarb > 18 mmol/L.

Place for bicarbonate infusion

Use of bicarbonate is controversial. Some studies suggest it may impair renal ketone clearance and paradoxically worsen ketosis.
Few indications for bicarbonate infusion:

• pH < 6.9
• life threatening hyperkalemia because HCO3 will drive K+ into cells.

Criteria for Severe DKA

#2021GM-JUL/Q25

#2021GM-JUL/Q27
Summary: Commonset neuromuscular junction disorder. Starts with eye symptoms. Can lead to myasthenic crisis. This can be precipitated by infections.

Commoner in females.

• Affects limbs as well. - proximal weakness (distal predominant weakness is rare), often asymmetrical.

• Presents as paraneoplastic syndrome of thymoma.
  May require prolonged ventilation.

#2021GM-JUL/Q24

EKG changes can include increased amplitude and width of P wave, T wave flattening and inversion, prominent U waves and apparent long QT intervals due to merging of the T and U wave and 'mild' ST depression.
The U-wave is a deflection following the T wave. . Potassium levels that are critically low (<1.7 mmol/L) can lead to torsades de pointes or“twisting of the points”, a polymorphic ventricular tachycardia.

[!INFO] U wave

• mechanism of generation isn't clearly identified
• normal u wave is concordant with the t wave
• it is smaller than the t wave (1/3 size)
• it's size increases with decreasing hear rate

Neurocysticercosis

#2022BSQ Q5

[!TIP] Mnemonic :"Solium polium" - solium = pork tapeworm.

ONLY TAENIA SAGINATA causes CYSTICERCOSIS.
Probably the most common parasitic infection of the CNS.
Pigs are the usual intermediate host, Humans are the definitive host.

cysticercosis results from humans acting as accidental intermediate hosts for the parasite

[!INFO] Humans eat pig meat -> taeniasis, Humans eat pig poop -> cysticercosis
Ingesting uncooked pork -> ingestion of cysts in pig muscle -> intestinal tape worm infection in the human.
Ingesting eggs in faeces from infected human -> cysticercosis -> possible neurocysticercosis.
In cysticercosis, eggs hatch into larva which migrate through the host body into various tissues.

Now found that most infections are asymptomatic. However, people infected with cysticercosis usually present due to the neurological symptoms.
Seizures are very common.
Diagnosis: Combintion of imaging and serology are required because there are situations in which only one of the two modalities will show positive results.
Imaging : MRI or CT, Serology: Immunoblot / enzyme linked assasy
Treatment:
Treatment of neurological symptoms with anticonvulsants, reducing cerebral oedema, intracranial pressure etc is the main concern.
Then, cysts are treated if required.
Calcified cysts are dead; antihelminthic therapy won't benefit the patient.
Live cysts: Antihelminthing treatment must be combimed with steroid which penetrates the BBB (Dexamethasone) to lessen the inflammatory response elicited following death of the parasite.

Granulomatous disease

Histologic pattern of chronic inflammation.
The particular pattern can suggestive of a particular disease

monocytes in blood -> become macrophages in tissue (aka histiocytes)
histiocyte = tissue macrophage

[!INFO] Granuloma formation: Overview
Granulomas are formed when individual macrophages can't eliminate an antigen.
Then antigen presenting cells in the tissue recruit more macrophages from the circulation into the tissue.
Macrophages all clump around the antigen forming a granuloma.
The macrophages undergo a process called epithelialization where they take on the appearance of epithelial cells.
There membranes beging to interdigitate and the nuclei swell.
Some of the macrophages will fuse to form Langhans giant cells.
The structure of the granuloma differs based on the triggering antigen.
In Tuberculosis, interferon gamma is a mediator of granuloma formation.
Other mediators like TNF-alpha are important in the formation of granulomas.

Metastasis in neoplasia

#2022BSQ Q2

Routes of malignant spread

1. Seedingof body cavities : Typical of ovarian CA
2. Lymphatic spread : more typical or carcinoma
3. Haematogenous spread: more typical or sarcoma.
   1. Arteries are less easily penetrated than veins. Mets occur along venous drainage.
   2. All portal drainage goes to the liver; all caval blood flows to the lung -> these capillary beds are the main sites of metastasis in haematogenous metastasis.
4. Thyroid and prostate CA metastasize via the paravertebral plexus -> vertebral metastases.
   1. bone metastases are more frequent in follicular and medullary thyroid cancers
5. Renal and hepatic CA like to grown inside veins:
   1. Renal - renal veins and IVC
   2. Liver hepatic veins and IVC
6. Path of venous drainage alone doesn't account for the distribution of particular metastatic tumours; Some tumours have a propensity to metastasize to particular organs. This may be due to chemoattraction or expression of tissue specific adhesion molelcules by tumour cells.
   1. prostatic carcinoma preferentially spreads to bone,
   2. bronchogenic carcinomas tend to involve the adrenals
   3. and the brain, and neuroblastomas spread to the liver and bones.

Brain tumours

Primary brain tumours are either

1. Glial tumours - airising from glial cells
2. Non glial - arising from everything else; nerves, blood vessels, glands etc.

Thyroid cancer

#2022BSQ-MAY Q27
Source:Medscape


Follicular cells : Papillary, follicular and anaplastic CA.
Parafollicular C cells : Medullary CA. (C cells are neuroendocrine cells and they produce [[Hormone Physiology#Calcitonin|Calcitonin]]).

Differentiated thyroid cancers

[!INFO] Hot nodules are almost always noncancerous
However, the majority of thyroid nodules scanned are (Approximately 95 percent) are cold**.
Most cold nodules are due to benign processes (>90%)
Cold nodules have an approximately 5% risk of being cancerous.
However, HOT nodules are almost never cancerous.

Both papillary and follicular CA are 3 times commoner in women.
Follicular develops at an older age.

Thyroglobulin is produced by differentiated thyroid CA. It can be used as a marker of recurrent after total thyroid ablation.

Papillary CA:

• Multifocality is a common pathological feature of PTC.
• Papillary carcinoma is a slow-growing tumor (has good prognosis) that arises from the thyroxine (T4)- and thyroglobulin-producing follicular cells of the thyroid.
• The cancer cells are TSH sensitive and take up iodine. They produce thyroglobulin in response to TSH stimulation
• Papillary CAs form non functional nodules. - Cold on scintigraphy.
• Histology: Unencapsulated; Consist of neoplastic epithelium growing on fibro vascular cores.
• Special nuclear features : emtpy nuclei ('orphan annie')
• Ability to invade adjacent lymphatics is a key feature.
• They tend to metastasize to the cervical lymph nodes.
• Haematogenous spread is rare but most common distant metastasis is to the lung.
• Factors which make a papillary CA high risk : Hx of head and neck radiation, male sex, age < 18 or > 55, + other obvious ones.

• Psammoma bodies are seen in papillary CA. (concentric, lamellated microscopic calcium deposits. They can be seen in other cancers and some benign lesions as well)

Follicular CA

Are also usually cold nodules on radioiodine scan.
Commoner in iodine deficient areas.

Histology: encapsulated.
Follicular cells have a solid, trabercular or follicular growth pattern.
No characteristic nuclear features.
No special nuclear features.
Differentiated from benign adenomas by

1. capsular invasion
2. vascular invasion

They arise from the follicular cells of the thyroid. The neoplastic cells are TSH sensitive as well, taking up iodine and producing thyroglobulin—a feature that is exploited diagnostically and therapeutically

Follicular carcinomas have less tendency for local metz (nodes) but higher risk of distant mets.

Distant mets for both types occur to lung and bone.

Hurthle Cell carcinoma

Hürthle cell carcinoma is a rare, more agrressive variant of follicular carcinoma. 5 year survival is 50 - 60%.
Makes up 2-3% of all thyroid malignancies.
Composed of distinct looking polygonal cells with acidophillic cytoplasm.
Associated with RAS mutation and RET/PTC oncogene.

[!INFO] Hurthle cells are seen in non malignant conditions as well
Hurthle cells are clasically seen in

• Hashimoto thyroiditis
• multinodular hypoplasia
• lymphocytic thyroidis
• Source

Medullary thyroid Cancer (MTC)

2-3% of thyroid CA.
They are associated with familial MTC (FMTC) syndromes.
So much so that there is a clinical distinction between identification of patient familial MTC and diagnosis a new sporadic MTC.

Parafollicular C cells produce calcitonin -> elevated calcitonin is diagnostic of MTC.
Inheritance of all familial forms of MTC and MEN2 are #autosomalDominant .
RET proto-oncogene mutations are seen in all MTC syndromes.

Familial cases are multifocal and bilateral.
Sporadic cases are unifolcal.

Histology:
unencapsulated.
Focal calcifications are present.
Characteristic depostion of amyloid is seen in the tumour. <- A unique features in thyroid malignancy.
C cell hyperplasia is unique to familial cases.

Treatment:
Lymph node metastasis is common.
Total thyroidectomy with lymph node clearance is done.
Prophylactic thyroidectomy is done in children diganosed with MEN2 syndromes.

FMTC syndromes:

1. MEN2A - pheochromocytoma, hyperparathyroidism.
2. MEN2B - MTC, phaechromocytoma, marfanoid habitus and galngioneuromatosis.
3. FMTC - only MTC.

In treatment of MEN, to avoid intra op hypertension, resection of pheochromocytoma should be done before MTC resection.

[!TIP] Mnemonic for MEN syndromes
පා පා පි
පා මේ ෆි
මා මේ ෆි

Anapalstic thyroid CA

[!WARNING] A very, very bad cancer!
It is rare but has the worst prognosis of all thyroid CAs.
Occurs in older adults (60-70) -> older adult with a thyroid nodule could have a dangerous thyroid CA.
1 year survival is a dismal 20%. Median survival is 5-6 months.

Anaplastic CA grows rapidly. Many patients present with local invasion (unresectable tumours) or cervial lymph node metastasis.

On histology, the tumour retains feature so epithelial cells (presence of desmosomes) but there are large areas of necrosis and bleeding. There is high mitotic activity.

Bone tumours

• In adults, bone mets are far more common than primary bone tumours.

• Bone is the 3rd commonest site of metastatis next to Lung and liver.

• Prostate and breast cancer (BC) are responsible for the majority of the skeletal metastases (up to 70%).

• Other sources of bone mets : thyroid, renal cell carcinoma, lung cancer, melanoma

Bone metastasis

Bone mets are commonest in spine, pelvis and thigh.

Osteolytic :

1. Multiple myeloma
2. RCC
3. melanoma
4. NSCLC
5. Non Hodgkin Lymphoma
6. thyroid cancer
7. Breast cancer

Osteoblastic:

1. prostate cancer,
2. carcinoid,
3. small cell lung cancer,
4. Hodgkin lymphoma
5. medulloblastoma.

Ignore breast in this list!

Regarding prostate CA:
Pathologic fractures do occur, although they are generally less frequent than in cancers with predominantly osteolytic disease
Source

Multiple myeloma – The classic bone lesions in multiple myeloma are purely osteolytic due to increased bone destruction and suppressed bone formation.

Prostate cancer – Males with bone metastases from prostate cancer predominantly have osteoblastic (aka sclerotic) lesions with increased numbers of irregular bone trabeculae. Simultaneously, osteoclastic action is also increased.

Breast cancer - The great majority of breast CA produces osteolytic bone lesions, osteoblastic areas are also usually present

Renal cancer also commonly spreads to bone.

Atherosclerosis

#2022BSQ Q8
Plaques are raised lesions in the blood vessel.
Filled with cholesterol and cholesterol esters.

Overview of atherosclerosis

Atherosclerosis requires two factors

1. Endothelial dysfunction
   1. Involving altered gene expression (eg. incr. adhesion molecules) and increased permeability of endothelial cells.
   2. This allows migration of blood monocytes into the intima where they become macrophages.
2. Increased lipids in the blood
   1. Cholesterol and it's esters are found inside plaques. They stimulate chronic inflammation in the intim in the presence of macrophages.

Anything that exacerbates these two factors will promote atherogenesis.

1. Endothelial damage and dysfunction
   1. Smoking, hypertension, flow turbulence, some infection, ?toxins and drugs
2. Hyperlipidaemia
   1. Any condition increases blood lipid levels ?Which lipids exactly - not HDL.

In the presence of lipids within the intima, macrophages become activated. When they engulf lipids, they become foam cells.
Cytokines secreted by macrophages stimulate altered function and growth of smooth muscle cells of the media.
Smooth muscle cells proliferate and take on fibroblastic roles.
Smooth muscles + collagen produced by them form the fibrous cap of the plaque.

Plaques can

1. obstruct vessels
2. rupture -> thrombosis
3. weaken the media -> aneurysms

Factors which make a plaque unstable:

1. Thin fibrous cap
2. Increased foam cells
3. Increased lipid content etc.

Pancreatic physiology

#2022BSQ Q24

Secretin and CCK are endocrine hormones.
Secretin - role is to neutralize stomach effluent

• peptide hormone
• produced by S cells of duodenum and brain
• inhibits gastrin release -> to reduce stomach acid production
• Stimulates pancreatic secretion of fluid and bicarbonate
  Cholecystokinin - promote pancreatic enzyme secretion, and gall bladder contraction.

Secretin stimulation test: Although secreting physiologically inhibits gastrin secretion, in the presence of a gastrinoma, secretin paradoxically increases gastrin secretion. This is the basis of the secretin stimulation test for gastrinoma.

Selected gastrointestinal regulatory peptides

#2022BSQ Q24

See table 32.4 K and C.
Secretin glucagon family
Vasoactive intestinal peptide (VIP) -> Secreted by enteric NERVES -> Neurotransmitter, Stimulates insulin release, splanchnic vasolidation and intestinal secretion of water and electrolytes; also relaxes smooth muscles, including the lower esophageal sphincter and colon

Glucose dependent insulinotropic polypeptide - GIP - - From duodenum, gastric antrum and ileum - stimulated by intraduodenal glucose -> incretin effect. (produced by K cells)

GLP-1 - The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, to limit postprandial glucose rise. Secreted by L cells in the ileum and colon.

Humans have almost no L cells proximal to the ligament of treitz (i.e in the duodenum) Source

Secretion is likely triggered by glucose in the duodenum as well as the rest of the gut as well. Source

GLP-1 physiology

Source
Only a small percentage of the produced GLP-1 reaches the liver and systemic circulation because of the action of DPP-IV.

[!TIP] All of these hormones generally cause changes which promote digestion and absorption except for somatostatin

Bilirubin physiology and elevations

CT

[!INFO] Significance of active conjugated bilirubin secretion from hepatocytes
The active secretion of cojugated bilirugin into bile cannaliculi is rate limiting. But uptake of unconjugated bilirubin is very efficient.
Therefore, hepatocytes near the supplying veins will take up all the unconjugated bilirubin but may not be able to excrete all of it into the bile. Therefore, they reexcrete it into the sinusoids so that down stream hepatocytes can reuptake this conjugated bilirubin and help to excrete it into the bile canalliculi.
I.e more hepatocytes are recruited for excretion.
The transport proteins requried for reabsorption are affected in Rotor syndrome -> leads to conjugated and unconjugated hyperbilirubinaemia.

Complement system overview

Source

[!INFO] Functions of complement

• Promote inflammation through C3a, C4a and C5a
• Recruit cells (through chemoatractants)
• Kill targeted cells (bacteria)
• Solubility antigen-antibody complexes and remove them from circulation

The alternative pathway of complement activation depends on spontaneous hydrolysis of C3 in plasma leading to the formation of C3 (H2O). This molecule binds to factor B. Subsequent activation by factor D results in the formation of C3 (H2O) Bb. This complex cleaves additional C3 to C3a and C3b constantly and at a low rate. In the presence of an activating surface (e.g. a bacterial wall), C3b is protected from inactivation by regulatory proteins like factor I and H. As a result the more active alternative pathway C3 convertase C3bBb is formed, which is further stabilized by properdin.Source

Causes of increased CPK

#2022BSQ Q31
CPK = CK.
Creatine Kinase is a catalyst for the formation of ATP from ADP via transfer of phosphate from creatine phosphate (which is an energy reservoir for muscle.
It is a very good indicator of muscle breakdown and it's progression.
CPK is eleminated by the Reticuloendothelial system. Serum level isn't elevated in kidney disease.

3 isoforms

• Skeletal muscle - 99% CK MM

• CK-MB = Usually in cardiac muscle. Can also be elevated in elite athletes and normal people after strenuous exercise (i.e can produce false +ve for MI)

• CK is usually elevated in myopathies. => there are different types of myopathies

  • Inflammatory myopathies - polymyositis / dermatomyositis
  • Drugs - colchicine (gout), antimalarials, statins, alcohol
  • Metabolic myopathies - carnitine palmitoyltransferase deficiency, Muscle phosphorylase deficiency (McArdle's disease)
    • McArdles disease - Autosomal recessive, exercise intolerance in childhood followed by cramps and myoglobinuria
  • Endocrine myopathies - hypothyroidism, acromegaly
  • Periodic paralyses - hours to days of muscle weakness with sharp rises of CPK; due to muscle membrane refractoriness secondary to ion shifts.
  • Neuroleptic malignant syndrome
  • Malignant hyperthermia - usually follows use of anaesthetic agents.

• Can also be elevated in a few non myopathic conditions

  • Exercise
  • Iatrogenic muscle injury
  • motor neuron disease
  • Asymptomatic elevation in CK

Urine cultures

We went to get urine samples which contain bacteria which have managed to enter the bladder. (bacteria colonize the distal urethra and genital mucosa)
Theoretical best sample is first voided urine of the day as bacteria have had time to multiply overnight and it is also the most concentrated sample.
Suprapubic taps should yield sterile urine in a healthy patient.

Prostatic massage should be done prior to urine sample correction in suspected if chronic bacterial prostatis is suspected. Massage should be avoided in acute bacterial prostatits -> risk of bactiraemia!

Sample is cooled until it is send to the lab to prevent bacterial multiplication affecting the colony count.

Urine microscopye

pyuria

8 cells / microL = 2-5 cells per High power Field.
Very high associated with urinary infection.

• bacteuria without pyuria -> usually means colonization rather than infection. (unless of course, patient is symptomatic)

White blood cell casts - renal infection = could be pyelonephritis.

Causes of sterile pyuria:

• False -ve for bacteria
  • Contamination with antiseptic
  • Atypical pathogens - Chlamydia, Ureaplasma urealyticum, or tuberculosis
• False +ve for leukocytes
  • Contamination with vaginal leukocytes
  • Chronic intersitial nephritis - omeprazole is a cause.
  • Nephrolithiasis
  • Uroepithial tumour
  • Intrabdominal inflammation adjacent to the bladder

Cardiac action potentials

Source: CVS physiology website.

Electrolyte effects on ECG

Hyperkalemia
EKG changes progress from peaked T-waves to widened QRS and eventually to ventricular tachycardia, fibrillation or pulseless electrical activity arrest.  These progressive changes can correlate with rising potassium levels. For example, peaked T waves might correspond with a potassium level of approximately 6 mmol/L, whereas cardiac arrest generally occurs at higher levels.

Hypokalemia
EKG changes can include increased amplitude and width of P wave, T wave flattening and inversion, prominent U waves and apparent long QT intervals due to merging of the T and U wave and 'mild' ST depression.
The U-wave is a deflection following the T wave. . Potassium levels that are critically low (<1.7 mmol/L) can lead to torsades de pointes or“twisting of the points”, a polymorphic ventricular tachycardia.

[!INFO] U wave

• mechanism of generation isn't clearly identified
• normal u wave is concordant with the t wave
• it is smaller than the t wave (1/3 size)
• it's size increases with decreasing hear rate

Hypercalcaemia
The most common EKG finding associated with hypercalcemia is shortening of the QT interval. In severe cases, Osborn or J waves might be seen or ventricular fibrillation might ensue. Recognition of these EKG findings can prompt urgent treatment.

Hypocalcemia
The most common finding on EKG in patients with hypocalcemia is a prolonged QT interval.

https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.105.166563

doi.org/10.1016/0002-9149(63)90255-8

Hypermagnesaemia

Tumour markers

#2021BSQ-JUL Q31

[!TIP] GPT answer:
Certainly! Here is a list of common tumor markers and the tumors they are commonly associated with:

1. Prostate-Specific Antigen (PSA) - Prostate cancer
2. Carcinoembryonic Antigen (CEA) - Colorectal cancer, pancreatic cancer, lung cancer
3. Alpha-fetoprotein (AFP) - Liver cancer, germ cell tumors, particularly testicular cancer
4. CA-125 - Ovarian cancer
5. CA 19-9 - Pancreatic cancer, colorectal cancer
6. CA 15-3 - Breast cancer
7. CA 27-29 - Breast cancer
8. Human Chorionic Gonadotropin (hCG) - Germ cell tumors, particularly testicular cancer, ovarian cancer, ?lung CA
9. Calcitonin - Medullary thyroid cancer
10. Thyroglobulin - Thyroid cancer (papillary and follicular)
11. Neuron-Specific Enolase (NSE) - Neuroendocrine tumors, small cell lung cancer
12. Chromogranin A - Neuroendocrine tumors
13. S-100 Protein - Melanoma, neuroendocrine tumors
14. Human Epidermal Growth Factor Receptor 2 (HER2) - Breast cancer, gastric cancer
15. Epidermal Growth Factor Receptor (EGFR) - Non-small cell lung cancer, colorectal cancer
16. 5 HIA - carcinoid tumour
17. Carcinoid tumors are of neuroendocrine origin and derived from primitive stem cells in the gut wall, especially the appendix.

BRCA1 and BRCA2 - breast and ovarian cancer.

Inflammatory bowel disease

[!TIP] A great summary!
Source

[!INFO] Differentiation of disease is vital to determine the potential effectiveness of surgery!
resection is curative in UC but disease recurs after resection in Crohn's

Peak incidence for both is between 15-30 years. Buy disease can occur at any age.

[!INFO] 'Positive features' of Ulcerative colitis not seen in Crohn's disease

• Toxic megacolon can occur.
• Marked pseudopolyps
• ? More malignant potential
• Rectal involvement is always present
• primary sclerosing cholangitis (seen mostly with UC)

Extraintestinal manifestations of Crohn's disease

1. Migratory arthitis - appendicular skeleton. Parallels intestinal disease. Treatment of intestinal disease resolves arthritis.
2. Perichonlangitis - seen on ERCP or MRCP.
3. Kidney stones
4. Bowel inflammation -> ureteric obstruction and hydronephrosis
5. Fistulas

Ileal resection can cause bile acid malabsorption -> diarrhoea.****

Primary sclerosing cholangitis

• Progressive and chronic liver disease caused by autoimmune mediated fibrosis of intra and extrahepatic bile ducts.
• Strongly associated with IBD (mainly ulcerative colitis)
• Associated with pANCA positivity.
• Often complicated by recurrent cholangitis and cholangiocarcinoma.
• Treament is not curative; it's aimed at minimizing symptoms and managing complications.
• Liver transplantation is the only treatment than can alter progression. Drugs won't work.
• Affects young to middle aged males (in their 40s)
  • PSC without IBD is more likely to occur in women.
  • PSC is seen predominantly in non smokers.
  • (Remember that smoking protects against ulcerative colitis! so if you smoke, you have less risk of UC and associated PSC)
• Ix: AST, ALT, GGT all elevated. Fluctuating conjugated hyperbilirubinaemia.
• hypergammaglobulinaemia is present.
• Best imaging modality: MRCP
• ultimately leads to cirrhocis.

Primary Biliary Cirrhocis / Primary Biliary Cholangitis

[!TIP] PBC - the C can stand for Cirrhocis or Cholangitis.

[!TIP] When to suspect
Suspect in a middle aged woman with pruritus who has elevated ALP and possible other autoimmune conditions.

[!TIP] Mnemonic: Don't confuse with PSC - PBC has 'cirrhocis' in the name -> live tissue is inolved -> interlobular bile ducts are involved.

MCQ Discussion:
Most often diagnosed through routine screening. Usually asymptomatic.
But Fatigue is a prominent presenting symptom. Icterus and pruritus are late signs.

• 95% of PBC occurs in women aged 40 - 50 years.

• There is destruction of small interlobular bile ducts.

• Antimitochondrial antibodies are found in all patients. M2 is specific for PBC.

  • The presence of serum antimitochondrial antibodies (AMA) is a highly specific indication of primary biliary cirrhosis (PBC).

• Presentation: Asymptomatic with #hepatomegaly and raised ALP. (raised ALP is often the only abnormal investigation)

• Pruritus and fatigue.

• Raised cholesterol and Xanthelasma

• Associated with many autoimmune conditions.

• Histology: portal tract infiltrate with hepatic granulomas; changes start in zone 1.

• 

Immunoglobulin / antibody classes

#2022BSQ BSQ Q49

Types of immunoglobulins and antibodies
IgG IgA IgD IgM IgE

Source

Insulin

#2022BSQ Q40

Sources of insulin

Animal based : not commonly used.
Bovine insulin differs from human by 3 amino acids, porcine by 1 amino acid.

Pharmacokinetics

Regular insulin and NPH insulin are considered older insulins.
Their time to peak and duration of action don't mimic physiologic secretion.

(U-100) denotes the usual concentration (100 U/ml).

Regular insulin

Duration: Short acting.
Controls post prandial glucose rise.
Same AA sequence as human insulin.
Bound to Zinc.
Hexamers must be converted to dimers and monomer before absorption -> leads to a delay in peak concentrations-> should be given 30 minuted before meals.
Duration of action tends to exceede duration of post prandial glucose rise -> risk of hypoglycaemia.

NPH insulin

Duration: Intermediate.
Suspension of human insulin, protamine and zinc. -> delays release of insulin into blood, also longer time to peak.
Patient must eat after the morning dose is given, to avoid hypoglycaemia.

Delivery :

mix immediately before injection and given at room temperature.
NPH insulin is a cloudy solution.
Can be mixed with regular or rapid acting insulins in the syringe.
Always draw up the regular(clear) insulin first to avoid contaminating the regular insulin with isophane insulin, thereby altering its pharmacokinetics.

U-500 insulin

Not regularly used nowadays, partly because of the advent of DPP-4 inhibitors.

Insulin analogs

made by recombinant DNA technology.
Subsitution of amino acids produces rapid acting and long acting analogs.

Rapid acting insulins

Lispro, aspart, glulisine (and faster aspart, lipro-aabc)
Duration: (very short) duration and rapid onset

modifications were made in the insulin molecule to prevent it from forming hexamers or polymers that slow absorption and delay action

Insulin aspart- substitution of aspartic acid for proline at position B28.

Insulin lispro is identical to human regular insulin except for a lysine and proline at positions B28 and B29.

Insulin glulisine has a lysine and glutamic acid at positions B3 and B29 respectively.

Rapid acting insulins are move convenient.
U-200 lispro and U-200 lispro-aabc, are high concentration preparations which have some niche use cases.

Basal insulin analogs

Determir

Insulin detemir – Detemir is an acylated insulin; the fatty acid side chain allows reversible albumin binding as well as concentration-dependent self-association (ie, formation of dihexamers) that results in prolongation of action.
Determir is much less potent - so it is formulated in a 4:1 ratio. (1 Unit of determir contains four times as many insulin molecules as any other preparation of insulin)
Can't mix with rapid acting insulins.

Glargine

Glargine is identical to human insulin except for a substitution of glycine for asparagine in position A21 and by the addition of two arginine molecules to the amino terminus.

After subcutaneous administration, glargine precipitates in the tissue, forming hexamers, which delays absorption and prolongs duration of action.

Glargine, which is in an acidic solution, cannot be mixed with rapid-acting insulins, as the kinetics of both the glargine and rapid-acting insulin will be altered

Glargine has less nocturnal hypoglycemia than NPH insulin

Duration of action : 24 hours but some may need twice daily dosing as half life is 12 hours. Unlike glargine, it has a small peak in it's concentration profile.

Higher concentration preparations of glargine (U-300) have an even flatter concentration curve with lower hypoglycaemic effect.

Degludec

form multimers from which monomers are release-> even longer duration of action.
Can mix with rapid acting insulins.

Determinants of insulin efficacy

• Site of injection - Limbs are faster than abdomen. (muscle-> increased blood flow)

  • 

  NPH insulin - leg or buttock preferred for moderate rate of absorption.
  Pre meal regular insulin - abdominal wall preferred for rapid absorption.

The absorption of the long-acting basal insulin analogs, glargine and degludec, do not appear to be significantly influenced by injection site

• Technique
  • Too shallow: intradermal injection that is not well absorbed.
  • Too deep: intramuscular -> rapid absorption
  • 4mm neele - can give perpendicular injection
  • 6mm needle - give at 45 degrees.
  • Rotate sites to avoid lipohypertrophy.
  • Injection through clothes won't cause dlivery problems but it means that skin cannot be inspected before injection -> not recommended.
• Size of the depot
  • Larger depot size - less overall absorption and more variability in absorption.
• subcutaneous blood flow
  • reduced by smoking
  • Increased by exercise and hot baths.
  • Variations not as significant with long acting insulins.

Types of hypersensitivity

#2022BSQ Q48
#2022BSQ-MAY Q46

Hypersensitivity reactions refer to undesirable responses produced by the normal immune system - Source

[!INFO] Mnemonic
Type III - 3rd letter in alphabet - C for immune complexes.
[[Toxicology#Serum sickness]]

Type 5 hypersensitivity

Is when the produced antibodies have the property of stimulating receptors on cells. Best example is Grave's disease.
Source

[!TIP] Hypersensitivity Vs Autoimmune disease
Hypersensitivity is an abnormal immune response to a harmless stimulus. When the 'stimulus' is a self antigen, we call it autoimmunity.

Autoimmune diseases can be classified in the same way as hypersensitivity conditions. but IgE is not involved in autoimmunity.
so in the table[[2022 November SBR]] below, there is no "type I" in the autoimmune categories

Autoimmune diseases examples

Autoimmune diseases caused by antigens against cell surface receptors: [[moreAutoimmuneDiseases.png]]

Infectious diarrhoea

#2022BSQ Q54

Diarrhoea in resource rich settings

• can be studied under inflammatory diarrhoeal causes and watery diarrhoeal causes.
  See mnemonics below:

[!INFO] A Great table!
[[diarrhoeaInResourceRichSettings.png]] <- A great table!

[!TIP] Watery diarrhoea
"Noninflammatory diarrhea is caused by the action of enterotoxins on the secretory mechanisms of the mucosa of the small intestine, without invasion" - Medscape.

Same day:

1. Norovirus
2. clostridium perfringens
3. possibly listeria (pregnancy, immunosuppression, extremes of age)

Next day:

1. E coli - enteroroxigenic
2. most other viruses - (1-3 days) diarrhoea in children, immunocompromised adults

Same week

1. Cyclospora

Weeks later

1. Giardia 1 to 2 weeks later - day care, swimming pools, travel / camping.
2. Cryptosporidium 2-28 days (upto 1 month after) - Associated with day care centers, swimming pools.

^5eaea3

[!TIP] Mnemonics: inflammatory diarrhoea
Fever, mucoid or bloody stools show infective diarrhoea:
"Can't Assume Everyone's Your Very Special Sidekick"

Let's break it down:

1. "Can't" - Campylobacter
2. "Assume" - Amoebiasis
3. "Everyone's" - E. coli
4. "Your" - Yersinia
5. "Very" - Vibrio parahaemolyticus
6. "Special" - Salmonella
7. "Sidekick" - Shigella

Most of these have P-incu of 1-3 days. But, entamoeba - much longer- 1 to 3 weeks, yersinia - slightly longer- 4-6 days, E-coli 1-8 days.

Diarrhoea in resource poor settings

Epidemic diarrhoea

Main two pathogens of epidemic diarrhoea

1. Cholera (secretory rice water diarrhoea) [[Misc infectious diseases#Cholera]]
2. Shigella dysenteriae (bloody diarrhoea) - SD1 serotype. (inflammatory diarrhoea - blood + mucous)

Non epidemic diarrhoea

Commonest causes of non epidemic watery diarrhoea - E. coli.

[!TIP] mnemonic
Acute bloody diarrhoea
$$
\Large{C^1S^2E^3}
$$

Commonest cause of non epidemic bloody diarrhoea - shigella flexneri (not dysenteriae)

• other causes of acute bloody diarrhoea
  • Campylobacter
  • Enteroinvasive E coli
  • Enterhemorrhagic E coli
  • Entamoeba histolytica
  • [[Misc infectious diseases#Schistosoma|Schistosoma mansoni]]

Diarrhoea due to preformed toxins

#2021BSQ-NOV Q37

Symptoms suggesting diarhoeal illness caused by preformed toxins:

• Absolutely Rapid onset of symptoms : within hours.
  • Bacteria which start to form toxin after ingestion take time to produce symptoms. (usually> 24 hours)
• Vomiting predominates in the clinical picture.
• Pathogens causing diarrhoea this way are
  • Staphylococcus aureas - Toxin is produced on food at room temperature; food doesn't taste or smell odd. Onset as rapid as Source 30 minutes!
  • and Bacillsu cereus

Enterobiasis

Pin worm.
Humans are considered the only host for E. vermicularis
Infection is commonest in children and institutionalised people.
Treatment is easy; reinfection is also easy.
Commonest symptom: itching in the perianal area, possible with excoriation and seconday bacterial infection.
Perianal itching / scratching contributes to faeco-oral transmission of the parasite.
Infection of the female genital tract can occur. Can cause abdominal pain mimicking appendicitis.
Treatment: Albendazole, mebendazole

Strongyloidosis

Strongyloides stercoralis : thread worm
First discovered in french troops returning from vietnam in the 19th century who developed chronic diarrhoea.
Infective stage : Filariform larva: -> penetrates intact skin.

[!INFO] How to understand the life cycle;
parasite has a free living cycle and parasitic cycle
Eggs can be deposited a) In the host intestine and b) in the environment.
Eggs always produce rhabditiform larvae.
Eggs -> rhabditiform larvae -> filariform larvae. (Infective stage) (autoinfection or otherwise).
If excreted with stool, rahbditiform larvae can go on to develop into adult sexual stages which produce more eggs in the free living cycle.

Female Adult worm (who live embedded in the submucosa of the small intestine) lays eggs.

It has been thought that the L3 larvae migrate via the bloodstream and lymphatics to the lungs, where they are eventually coughed up and swallowed. However, L3 larvae appear capable of migrating to the intestine via alternate routes (e.g. through abdominal viscera or connective tissue)

Symptoms:

Respiratory : Dry cough - about 1 week after infection
Abdominal pain, bloating, intermittent constipation and diarrhoea - about 3 weeks or later after infeciton (due to infection of the small intestine)
Skin: Itchy rash at site of entry; recurrent red rash along thighs and buttocks. - Larva currens (pathognomonic of Strongyloidiasis).
Disseminated life threatening infection can occur in immunosuppressed people.
Eosinophilia(+)

Management:

Ivermectin has been shown to be superior to albendazole.

Ivermectin: binds selectively and with high affinity to glutamate-gated chloride ion channels in invertebrate muscle and nerve cells of microfilaria.

Albendazole and other similar drugs inhibit the beta tubulin of worms (intracellular cytoplasmic structural protein) -> immobilization and death.

Skull base fracture

#2022BSQ Q51
Skull base fracture and associated injuries; Source
NCBI article <- good link
Cranial nerve injuries: Page 1079 of Moore's clinical anatomy.

Sjogren syndrome

#2022GM Q14
#2021GM-JUL/Q17

Pathogenesis: Autoimmune disease affecting exocrine glands.

In most cases, Sjogren syndrome is only 'irritating' and not dangerous.

Can occur as a primary disorder or secondary to another rheumatic disease.

Symptoms are classified mainly as

1. Exocrine gland symptoms
   1. Predominant symptoms of Sjogren's syndrome are
      1. oral dryness (affects salivary glands)
      2. and dry eyes. - assessed by Schirmer test < 5mm/min. (filter paper used to assess tear production)
2. Extra glandular symptoms
   1. Skin :
      1. Xerosis (dryness)
      2. Raynaud's phenomenon
      3. Cutaneous vasculitis: Palpable purpura is the commonest manifestation.
   2. Muskuloskelatal: Arthralgria, myopathy, fibromyalgia.
   3. Associated with autoimmune thyroiditis.
   4. Lungs - interstitial lung disease; upper and small airway involvement; Patients have cough and dyspnoea.
   5. Peripheral neuropathy
   6. Depression / mood changes/ mild cognitive impairment (maybe due to poor sleep)
   7. Mild anaemia and leukopenia
   8. Other autoimmine diseases
      1. Myasthenia gravis
      2. Autoimmune hepatitis/ pancreatitis.
   9. Increased incidence of Non Hogdkins B lymphoma.
   10. Can cause renal involvement - hypokalemia is common secondary to distal renal tubular acidosis[[2021-SBR-November#Renal tubular acidosis]] with K+ wasting.
   11. Rare complication of Sjogren syndrome during pregnancy : congenital heart block.
   12. ?Dysphagia with abnormal oesophageal motility.

Spectrum of disease:

Mild disease : just dry eyes and mouth; Requires diagnostic criteria to be fullfilled to diagnose SjD.

Severe disease:
A severely affected patient may have florid salivary gland enlargement, adenopathy, antibodies to the Ro/SSA and La/SSB antigens, cryoglobulinemia, hypocomplementemia, a propensity to develop non-Hodgkin lymphoma, and other extraglandular disease manifestations.

90% are positive for Rheumatoid factors: Kumar and Clark

Epidemiology: Most Commonly occurs in women aged 50-60 years old.

Associated conditions

Keratoconjuntivis sicca - term for the occular manifestations of Sojgrens.
Mikulicz syndrome: Parotid and lacrimal gland enlargement; Sojgren's disease is one possible cause of this.

Diagnostic criteria:

Biopsy showing focal lymphocytic infitrate of labial salivary glands. Termed Focal lymphocytic sialadenitis.
Objective test: Focal lymphocytic sialadenitis score >= 1;

Anti Ro/SSA and anti La / SSB positivity suggests Sojgren's disease.

Background of systemic autoimmune disease. -
The most common associations are SLE and Rheumatoid arthritis.

Pathogenesis of ascites in Cirrhocis

Several haemodyanic and vascular changes occur which contribute to the formation of cirrhocis.

Vascular:

• Decreased peripheral resistance (and reduced arterial pressure)
  • (most apparent in the splanchnic circulation)
• Increased circulatory volume
• Increased cardiac output (and tachycardia)
• Increased portal blood flow
• I.e Hyperdynamic circulation is present.
  but, with
• Decreased renal perfusion (kidneys compensate by increasing their production of prostacyclin - a vasodilator. This effect is lost in patients with hepatorenal syndrome and can be inhibited iatrogenically by NSAIDS -> both causing a ==disastrous== fall in renal plasma flow!)

Multiple mediators have been studied as sources of the systemic vasolidation but the most important one seems to be increased NO synthesis.

inhibition of synthesis of NO in rats restores normal arterial pressure.

? cause for increased NO
Portal hypertension -> increased portosystemic shunting -> decreased hepatic clearance of bacterial toxins / DNA absorbed from GI tract.

mediated by vascular changes:
Splanchnic vasodilation
Renal artery vasoconstriction
(and also pulmonary vasodilation)

Ascites: The pathological accumulation of fluid in the peritoneum.
Development of portal hypertension is the first step and is essential for the formation of ascites in cirrhocis.

Older theories of ascities formation : undefill theory and overflow theory. Modern arterial vasodilation hypothesis fits better with data.

Arterial vasodilation theory of ascites formation

A portal pressure >12 mmHg appears to be required for fluid retention
Portal hypertension is not simply due to mechanical obstruction of the portal system. It occurs due to increased flow from the splanchnic arteries.

See hypothesis-highlights on UpToDate

SAAG

#2022GM Q32
Serum 'to' Ascites Albumin gradient

SAAG > 11g/L - low protein in ascitic fluid => Suggest portal hypertension as cause; (i.e transudate)
SAAG < 11g/L - high protein in ascitic fluid (or low serum protein) => Exudate (?malignancy)

Low ascitic fluid protein may increase the risk of SBP as there are no opsonins in the fluid to combat infection.

Liver transplantation

Indications for liver transplantation

1. Acute liver failure of any cause
2. Chronic hepatic failure with Childs grade > C or MELD > 20;
   1. hepatopulmonary syndrome can be reversed by hepatic transplantation.
3. Primary biliary cholangitis
4. Chronic hepatitis B is HBV DNA negative or falling; recurrence of infection is prevented by HBIG and nucleoside analogues.
5. Autoimmune hepatitis
6. Alcoholic
7. Metabolic disorders - haemochromatosis, Wilsons, Alaph a antitrypsin deficiency
8. NASH cirrhocis

Bronchiectasis

#2022GM Q21

Review of airway histology

Respiratory epithelium - ciliated pseudostratified columnar epithelium.

Note the presence of smooth muscle and it's decreasing thickness as the airways become smaller.

Bronchioles - intralobular airways < 1mm in diameter arising roughly after the 10th generation of branching.

Epidemiology

Commoner in women.
Increases with age; marked increase after 60 years.

Pathology

Bronchiectasis is the permanent dilation of bronchi and
bronchioles caused by destruction of the muscle and the
supporting elastic tissue, resulting from or associated with
chronic necrotizing infections. It is not a primary disease
but rather secondary to persisting infection or obstruction
caused by a variety of conditions

Obstructive impairment (ie, reduced or normal FVC, low FEV1, and low FEV1/FVC) is the most frequent finding on spirometry. ;
$$
\LARGE{Obstruction = ↓\frac{FEV_{1}}{FVC}}
$$

See [[Lung function tests#Obstructive vs. restrictive diseases]]

Morphology

Usually affects bilateral lower lobes.
Permanent dilation -> small airways are traceable almost upto the pleura. (in normal lungs, they stop about 2 cm short of the pleura)
Chronic inflammatory exudate is seen.
Extensive desquamation of epithelium causing ulceration.
Healing is usually by fibrosis.
Abscesses can form as complications.

Diagnosis:

Clinical and CT:
CT features that are reliable signs of bronchiectasis:

• Airway-to-arterial ratio ≥1.5 (internal airway lumen diameter/adjacent pulmonary artery diameter)
• Lack of tapering of bronchi (tram track appearance)
• Airway visibility within 1 cm of a costal pleural surface or touching the mediastinal pleura

Causes of bronchiectasis and basis of disease

Common causes

Obstruction - tumour, lymph nodes, aspiration etc. <- impaired drainage
Inherited disorders -
Cystic fibrosis <- impaired clearance of mucous
Kartagener syndrome <- Ciliary impairement
Autosomal recessive #autosomal-Recessive
Situs inversus, chronic sinusitis, and bronchiectasis; Underlying pathology is primary ciliary diskinesia. Kartagener Xn is a subset of primary ciliary diskinesia (in which patients may not have situs inversus).
Screening test -> patients have low levels of nasal nitric oxide.

Immunoglobulin deficiencies <- recurrent infection
Necrotizing of suppurative pneumonia - staph aureus or klebsiella <- scarring and impaired clearance; ?exagerrated neutrophil response

Other causes

Young syndrome - similar to CF but no evidence of CF; rare diagnosis nowadays.
Associated with two rheumatic disorders - Sjogren syndrome and Rheumamtoid arthritis.
[[General Medicine 1#Allergic bronchopulmonary aspergillosis|Allergic bronchopulmonary aspergillosis]] - ? central bronchiectasis

Management

Antibiotics for exacerbations
Control of acute bleeding with bronchoscopic local therapy or bronchial artery embolization.
Refractory disease: surgical therapy - ? resection

Immunodeficiency syndromes

• Primary immunodeficiencies arise from inborn defects. They usually present in childhood.
  • Common variable immunodeficiency is a notable exception to this.
• Seconday immunodeficiency is far more common (?in adult populations)
  • Diabetes mellitus
  • Human immunodeficiency virus (HIV) infection
  • Cirrhosis
  • Nephrotic syndrome
  • Other protein-losing states, such as enteropathies, severe exudative skin disease including burn injury, and peritoneal dialysis
  • Malnutrition
  • Hemoglobinopathy
  • Inflammatory bowel disease or rheumatoid arthritis receiving immunosuppressive therapies (particularly tumor necrosis factor [TNF] inhibitors)
  • Neurologic disease
  • Autoimmune disease
  • Splenectomy
  • Malignancy
  • Radiation therapy
  • Immunosuppressive agents, such as glucocorticoids and others
  • Immunomodulatory agents, such as rituximab, etanercept, and others

Typical presentations and associated defects in the immune system

#2022BSQ-MAY Q49

Skin infections, in isolation, are not usually indicative of an underlying primary immunodeficiency.
Chronic mucocutaneous candidiasis - ussually begins in childhood; associated with several immunodeficiency states; usually doesn't show systemic infection with the fungus.
Recurrent herpevirus infection / reactivation -> These individuals should be evaluated for underlying T or natural killer (NK) cell dysfunction. See -> [[2021 Basic Sciences July#Natural killer cells]]
 ***
 However, recurrent respiratory tract infections in combination with more serious infections are a classic presentation of antibody deficiencies.
 ***
~~>  
 - Isolated urinary tract infections are more suggestive of anatomic defect than immunodeficiency.
 - Relapsing, recurrent, and/or progressive enterocolitis due to common enteropathogens, such as Giardia, enteroviruses, cytomegalovirus, and campylobacter, are associated with underlying hypogammaglobulinemia and/or T cell immunodeficiency.
 
 - Recurrent Neisseria meningitidis meningitis -> Deficiency of one or more of the terminal complement components (C5, C6, C7, C8, C9) . Low complement levels may be due to either congenital complement deficiency or acquired diseases, such as systemic lupus erythematosus.
 - Immunoglobulin deficiency disorders or impaired reticuloendothelial function resulting from splenectomy or hemoglobinopathy are associated with an increased risk of bacteremia and meningitis due to encapsulated pathogens.
 - Marked elevation of serum IgE with multisystem infections -> Job syndrome
~~

Immunoglobulin / antibody deficiencies

Usually due to defects in B lymphocytes -> not enough antibodies produced.

Recurrent sinopulmonary infections and persistence of gut pathogens.
Leads to bronchiectasis and chronic diarrhoea with malabsorption.

Common variable immunodeficiency

[!INFO] Commonest significant antibody deficiency affecting children and adults.

Diagnosed at: 20 and 45 years of age.

? etiology - few are inherited. Pattern may by #autosomalDominant with low penetrance or #autosomal-Recessive - UpToDate

There is

• B cells are present but they don't produce antibodies (i.e are ?nonfunctional?)
  • B cell numbers are normal but there are low levels of isotype switched B memory cells and plasma cells.
• Low levels of all immunoglobulin classes
• Frequent bacterial infections.

Lymphoma is a common cause of death in these patients.

Complications:

• Recurrent infections - sinopulmonary (with encapsulated Streptococcus pneumoniae and Haemophilus influenzae and others) -> can lead to bronchiectasis.
• Autoimmune disorders - RA, vitiligo, haemolytic anaemia.
• Lymphoma

Chronic giadia infections with malabsorption can occur.

Treatment is IVIG.

Selective IgA deficiency

Commonest primary immune deficiency.
Individuals are usually asymptomatic. -> treatment is only antibiotics as needed.
Can present with recurrent mucosal pyogenic infections.

Agammaglobulinaemia

#2021BSQ-JUL Q24
Also called hypogammaglobulinaemia.

Mutation of the BTK gene impairs B cell maturation -> causes low or absent mature B cells -> severe hypogammaglobulinaemia.
Commonest inheritance: #x-linked-recessive with mothers being carriers. #autosomal-Recessive inheritance is seen in ? 50%. - confirm

Manifestation: recurrent sinopulmonary infections.(From 6 to 12 months of age, otitis media, sinusitis, bronchitis, and pneumonia).
Common pathogens: Encapsulated pyogenic bacteria Haemophillus influenzae and strep pneumoniae.

Treatment: repeated IVIG transfusions or stem cell transplant.

Complement deficiency

[[2022-November#Complement system overview]]
Impaired alternative pathways -> non specific impairement -> bacterial infections.

Impaired classical pathway -> increased infection and increased immune complex deposition -> SLE, vasculitis, glomerulonephritis etc.

MAC -> neisseria infections.

Severe combined immunodeficiency - SCID

#2022BSQ-MAY Q49

• Commonest form is impaired #x-linked-recessive .

• Defect is in IL-2 receptor.

  • IL-2 is a cytokine which causes proliferation of T lymphocytes specific to a particular antigen. (Figure 4-4 Robbins)

• T and NK cells are lacking in the blood.

• Presentation is similar to pure T lymphocyte deficiency:

• That is, infections with fungi, protozoa, intracellular organisms.

• persistent and recurrent diarrhoea, otitis media, thrush, and respiratory infections

• Treated with Stem Cell transplant.
• Presents before 3 months of age; without treatment babies die before 2 years of age.

Immune response to fungi

[[ImmuneResponsesTofungalpathogens.pdf]]
Not as well understood as bacteria and viruses.
Pattern recognition receptors (PRR) on antigen presenting cells are triggered by fungal cell components.
This causes intracellular signalling of the APC which promotes phagocytosis and stimulates killing mechanisms.
The adaptive immunity to fungi is mediated by CD4+ Th1 cells with produce interferron gamma and CD4+ Th17 cells which produce IL-17. They drive killing by innate effector cells like marcophages and neutrophils.

So overall,

1. neutrophil defects cause systemic candiasis
2. T cell defects cause mucocutaneous candidiasis.

OPSI - overwhelming post splenectomy infection

Splenectomy leaves the patient vulnerable to infection by capsulated organisms.

1. Streptococcus pneumoniae
2. Haemophillus influenzae
3. Neisseria meningititis

More than half of those with OPSI die.

Why specifically encapsulated organisms?

Encapsulated organisms are resistant to phagocytosis without opsonization.
The spleen is a major site of early IgM production.

IgM memory B cells produce IgM to promote the clearance of polysaccharide-encapsulated bacteria.

Although the total B lymphocytes remain intact, a significant fall in the levels of memory B cells and switched B cell proportions are usually encountered 150 days post-splenectomy. This acts as a particular predisposition to infections caused by polysaccharide-encapsulated bacteria and is responsible for a diminished immunological response to polysaccharide vaccines
Source

However, even after opsonization, the bacteria must be phagocytosed. Splenic macrophages are a major contributor to this phagocytosis.
So in asplenia, there is impaired IgM production and thus opsonization and also impaired phagocytosis.

Amyloidosis

"Amyloid" was meant to describe the starch like properties of the substance. Initially described as "waxy" and "lardaceous".

Subtypes of amyloidosis

There are 18 different types of systemic and 22 localized forms of amyloidosis

The four most common causes of systemic amyloid deposition are

1. AL amyloidosis
2. ATTRwt - wild type transthyretin amyloidosis
3. Hereditary (famliliarl) amyloidosis
4. AA amyloidosis

[!INFO] AL Vs AA : importance of differentiating
AL amyloidosis must be differentiated from other forms of amyloidosis (eg, AA amyloidosis, ATTRmt amyloidosis, and ATTRwt amyloidosis) since the latter are non-neoplastic and will not benefit from chemotherapy.

Other forms of amyloidosis:

• Heritable amyloidosis types
• Organ specific amyloidosis
• Dialysis related amyloidosis

Diagnosis

Histological : Fat pad biopsy (less risk of bleeding)
Organ biopsy is needed if a specific organ is involved.

When congo red stains binds to amyloid protein, it produces apple green birefringence.

Looks similar to DM nephropathy but the staining characteristics are different (DM nephropathy is PAS and silver stain positive)

Cutaneous manifestations of amyloidosis

• purpura, petechiae, and ecchymoses following minor trauma ("pinch purpura")
• Appearance of periorbital purpura following a Valsalva maneuver or dependent positioning of the head. Macroglossia (picture 16), waxy papules and plaques, enlarged shoulder pads, bullous lesions, and sclerodermatous changes in the skin may also be seen. (UpToDate)

AL amyloidosis

AL amyloidosis is Associated with plasma cell dyscrasia (multiple myeloma, waldenstrom macroglobulinemia)

Symptoms and signs

There is multisystem amyloid deposition

• Fatigue, non intentional weight loss

• Heavy proteinuria (70%) - nephrotic syndrome

• oedema

• #hepatosplenomegaly (hepatomegaly +/- splenomegaly seen in 70%)

• Cardiomyopathy and heart failure (60%) - thickening of interventricular septum is present / MI due to accumulation of amyloid in coronaries.

  • Cardiomyopathy is common in AL and ATTR but rare in AA amyloidosis

• Neuropathies - carpal tunnel, mixed sensory and motor peripheral neuropathy is a prominent feature in AL amyloidosis. (Symptoms of numbness, paresthesia, and pain are frequent)

• Amyloid infiltration of muscles - macroglossia with scalloping and shoulder pad sign. (also enlarged deltoids)

• Skin - purpura (raccoon eyes with valsalva maneuver is specific), waxy skin, easy bruising.

• Coagulopathy - possibly due to factor X binding of coagulation factors to amyloid.

• GI involvement: gastroparesis, constipation, bacterial overgrowth, malabsorption, and intestinal pseudo-obstruction resulting from *dysmotility

  Criteria for organ involvement

Treatment

Bortezomi based induction
Melphalan
Haematopoietic cell transplantation.

Prognosis

This disorder has a poor long-term prognosis, with cardiac or hepatic failure, and infection being the major causes of death
Earlier detection confers better outcome.

AA amyloidosis

The most common organ affected by AA amyloid is the kidney (approximately 80 percent of patients -> causes nephrotic syndrome.

AA amyloidosis may complicate chronic diseases in which there is ongoing or recurring inflammation, such as rheumatoid arthritis (RA), spondyloarthritis, or inflammatory bowel disease; chronic infections.

Symptoms

SImilar to AL (but cardiomyopathy is rare)
GI involvement: similar to AA amyloidosis

Treatment

In untreated patients, AA (secondary) amyloidosis carries a significant risk of mortality due to end-stage kidney disease, infection, heart failure, bowel perforation, or gastrointestinal bleeding.
Successful treatment of the underlying inflammatory process improves kidney function.

Spondyloarthritis (SpA)

Spondylos = greek for vertebrae

common features

• chronic low back pain
• positivity for HLA B27 antigen (present in 90% of those with AS)
  • (However, there is high background positivity of approx 8% so HLA isn't usually used in diagnosis. )
• radiographic changes in the sacroiliac joints in patients with axial SpA
• and asymmetric (oligo)arthritis, heel enthesitis and dactylitis in patients with peripheral SpA
• uveitis, inflammatory bowel disease, psoriasis, and increased levels of acute phase reactants

Uveitis
The presence of leukocytes in the anterior chamber of the eye is characteristic of anterior uveitis.
The presence of leukocytes in the vitreous humor - intermediate uveitis
Evidence of active chorioretinal inflammation -> posterior uveitis

• Rheumatoid factors negative. (<- Seronegative arthropathies)

characteristic radiographic features

Sacroiliac joint:
sclerosis,
joint space widening, or erosion (fusion in late stages)
syndesmophytes and changes of spondylitis in the spine, which are most often detected in more longstanding disease.

A syndesmophyte is a bony growth originating inside a ligament, commonly seen in the ligaments of the spine, specifically the ligaments in the intervertebral joints leading to fusion of vertebrae.

Inflammatory osteoproliferative lesions in the spine are called syndesmophytes (marginal and non-marginal), and degenerative osteoproliferative lesions are called osteophytes. Syndesmophytes are more vertically oriented than osteophytes.

subtypes of SpA

• Ankylosing spondylitis
• Psoriatic arthritis
• Reactive arthritis
• IBD related arthritis
• And some other types
  • nonradiographic axial SpA (nr-axSpA), peripheral SpA,

#TODO add image of enthesis

Ankylosing spondylitis

#2022GM Q25
#2022GM Q27

Ankylosing = stiffness or fixation of a joint by disease

Affects teens to early 30s, male >> female (5:1).
Pathology: lymphocyte and plasma cell infiltration of the attachments of ligaments. (enthesitis)

Some terminology: not super important

Pathogenesis of AS

SourceGreat article!
HLA-B27

[!INFO] Key points

• It's largely a genetic disease - Patient's children have increased risk of getting it
• Pathogenesis consists of inflammation, bone erosion and syndesmophyte formation.
• Bone erosion and syndesmophyte formation are probably not linked to inflammation
• TNF-blockage suppresses symptoms but doesn't arrest bone changes.
  
  

Clinical features of AS

• Intermittent episodes of sacroiliac joint inflammation
  • Chronic back pain which is reduced by exercise.
• Uveitis and costochondritis suggest back pain of rheumatic origin (i.e AS)
• Peripheral Joint involvement is asymmetrical and involves the large joints.
  • (eg Hip)
  • ankles, hips, knees, shoulders, and the sternoclavicular joints
• Axial joints
  • Formation of syndesmophytes can lead to fusion of vertebrae. (Shobers test detects a stiff spine in early stages)
  • Advanced cases: fusion of the sacroiliac joints, and bamboo spine. (Gadolinum MRI is more sensitive than Xray at detecting early changes).
• Dactylitis - sausage shaped fingers and toes
• Extra-articular manifestations
  • Uveitis - can present as painful eye with photophobia and blurred vision -> emergency!
  • Aortitis

Management of Anky Spondi

• Prevention of syndesmophyte formation -> early diagnosis and initiation of exercise regimen.
• NSAIDS for pain relief to enable exercise during exacerbations.
• MTX -> good for peripheral arthritis but will not work for spinal disease. Only exercise👆
• TNF-α blockers - etanercept and adalimumab provide HUGE symptomatic relief. They reduced morbidity
• Children of affected person have a 30% change of developing anky Spondi.
• Overall prognosis is good with exercise and pain relief, allowing 80% of patients to remain employed.

Aplastic anaemia

#2022GM Q30
Congenital

• fanconi anaemia

• dyskeratosis congenita
• Familiar aplastic anaemia
• Cartillage hair hypoplasia
• Diamond-blackfan anaemia

Acquired

• infection - EBV, hepatitis, parvovirus, mycobacteria
• Ionizing radiation
• Benzene, pesticides
• GVHD
• Pregnancy
• anorexia, severe nutritional deficiencies
• PNH

Hepatosplenomegaly and lymphadenopathy are rare.

Neurocysticercosis

#2022BSQ Q5

[!TIP] Mnemonic :"Solium polium" - solium = pork tapeworm.

ONLY TAENIA SAGINATA causes CYSTICERCOSIS.
Probably the most common parasitic infection of the CNS.
Pigs are the usual intermediate host, Humans are the definitive host.

cysticercosis results from humans acting as accidental intermediate hosts for the parasite

[!INFO] Humans eat pig meat -> taeniasis, Humans eat pig poop -> cysticercosis
Ingesting uncooked pork -> ingestion of cysts in pig muscle -> intestinal tape worm infection in the human.
Ingesting eggs in faeces from infected human -> cysticercosis -> possible neurocysticercosis.
In cysticercosis, eggs hatch into larva which migrate through the host body into various tissues.

Now found that most infections are asymptomatic. However, people infected with cysticercosis usually present due to the neurological symptoms.
Seizures are very common.
Diagnosis: Combintion of imaging and serology are required because there are situations in which only one of the two modalities will show positive results.
Imaging : MRI or CT, Serology: Immunoblot / enzyme linked assasy
Treatment:
Treatment of neurological symptoms with anticonvulsants, reducing cerebral oedema, intracranial pressure etc is the main concern.
Then, cysts are treated if required.
Calcified cysts are dead; antihelminthic therapy won't benefit the patient.
Live cysts: Antihelminthing treatment must be combimed with steroid which penetrates the BBB (Dexamethasone) to lessen the inflammatory response elicited following death of the parasite.

Granulomatous disease

Histologic pattern of chronic inflammation.
The particular pattern can suggestive of a particular disease

monocytes in blood -> become macrophages in tissue (aka histiocytes)
histiocyte = tissue macrophage

[!INFO] Granuloma formation: Overview
Granulomas are formed when individual macrophages can't eliminate an antigen.
Then antigen presenting cells in the tissue recruit more macrophages from the circulation into the tissue.
Macrophages all clump around the antigen forming a granuloma.
The macrophages undergo a process called epithelialization where they take on the appearance of epithelial cells.
There membranes beging to interdigitate and the nuclei swell.
Some of the macrophages will fuse to form Langhans giant cells.
The structure of the granuloma differs based on the triggering antigen.
In Tuberculosis, interferon gamma is a mediator of granuloma formation.
Other mediators like TNF-alpha are important in the formation of granulomas.

Metastasis in neoplasia

#2022BSQ Q2

Routes of malignant spread

1. Seedingof body cavities : Typical of ovarian CA
2. Lymphatic spread : more typical or carcinoma
3. Haematogenous spread: more typical or sarcoma.
   1. Arteries are less easily penetrated than veins. Mets occur along venous drainage.
   2. All portal drainage goes to the liver; all caval blood flows to the lung -> these capillary beds are the main sites of metastasis in haematogenous metastasis.
4. Thyroid and prostate CA metastasize via the paravertebral plexus -> vertebral metastases.
   1. bone metastases are more frequent in follicular and medullary thyroid cancers
5. Renal and hepatic CA like to grown inside veins:
   1. Renal - renal veins and IVC
   2. Liver hepatic veins and IVC
6. Path of venous drainage alone doesn't account for the distribution of particular metastatic tumours; Some tumours have a propensity to metastasize to particular organs. This may be due to chemoattraction or expression of tissue specific adhesion molelcules by tumour cells.
   1. prostatic carcinoma preferentially spreads to bone,
   2. bronchogenic carcinomas tend to involve the adrenals
   3. and the brain, and neuroblastomas spread to the liver and bones.

Brain tumours

Primary brain tumours are either

1. Glial tumours - airising from glial cells
2. Non glial - arising from everything else; nerves, blood vessels, glands etc.

Thyroid cancer

#2022BSQ-MAY Q27
Source:Medscape


Follicular cells : Papillary, follicular and anaplastic CA.
Parafollicular C cells : Medullary CA. (C cells are neuroendocrine cells and they produce [[Hormone Physiology#Calcitonin|Calcitonin]]).

Differentiated thyroid cancers

[!INFO] Hot nodules are almost always noncancerous
However, the majority of thyroid nodules scanned are (Approximately 95 percent) are cold**.
Most cold nodules are due to benign processes (>90%)
Cold nodules have an approximately 5% risk of being cancerous.
However, HOT nodules are almost never cancerous.

Both papillary and follicular CA are 3 times commoner in women.
Follicular develops at an older age.

Thyroglobulin is produced by differentiated thyroid CA. It can be used as a marker of recurrent after total thyroid ablation.

Papillary CA:

• Multifocality is a common pathological feature of PTC.
• Papillary carcinoma is a slow-growing tumor (has good prognosis) that arises from the thyroxine (T4)- and thyroglobulin-producing follicular cells of the thyroid.
• The cancer cells are TSH sensitive and take up iodine. They produce thyroglobulin in response to TSH stimulation
• Papillary CAs form non functional nodules. - Cold on scintigraphy.
• Histology: Unencapsulated; Consist of neoplastic epithelium growing on fibro vascular cores.
• Special nuclear features : emtpy nuclei ('orphan annie')
• Ability to invade adjacent lymphatics is a key feature.
• They tend to metastasize to the cervical lymph nodes.
• Haematogenous spread is rare but most common distant metastasis is to the lung.
• Factors which make a papillary CA high risk : Hx of head and neck radiation, male sex, age < 18 or > 55, + other obvious ones.

• Psammoma bodies are seen in papillary CA. (concentric, lamellated microscopic calcium deposits. They can be seen in other cancers and some benign lesions as well)

Follicular CA

Are also usually cold nodules on radioiodine scan.
Commoner in iodine deficient areas.

Histology: encapsulated.
Follicular cells have a solid, trabercular or follicular growth pattern.
No characteristic nuclear features.
No special nuclear features.
Differentiated from benign adenomas by

1. capsular invasion
2. vascular invasion

They arise from the follicular cells of the thyroid. The neoplastic cells are TSH sensitive as well, taking up iodine and producing thyroglobulin—a feature that is exploited diagnostically and therapeutically

Follicular carcinomas have less tendency for local metz (nodes) but higher risk of distant mets.

Distant mets for both types occur to lung and bone.

Hurthle Cell carcinoma

Hürthle cell carcinoma is a rare, more agrressive variant of follicular carcinoma. 5 year survival is 50 - 60%.
Makes up 2-3% of all thyroid malignancies.
Composed of distinct looking polygonal cells with acidophillic cytoplasm.
Associated with RAS mutation and RET/PTC oncogene.

[!INFO] Hurthle cells are seen in non malignant conditions as well
Hurthle cells are clasically seen in

• Hashimoto thyroiditis
• multinodular hypoplasia
• lymphocytic thyroidis
• Source

Medullary thyroid Cancer (MTC)

2-3% of thyroid CA.
They are associated with familial MTC (FMTC) syndromes.
So much so that there is a clinical distinction between identification of patient familial MTC and diagnosis a new sporadic MTC.

Parafollicular C cells produce calcitonin -> elevated calcitonin is diagnostic of MTC.
Inheritance of all familial forms of MTC and MEN2 are #autosomalDominant .
RET proto-oncogene mutations are seen in all MTC syndromes.

Familial cases are multifocal and bilateral.
Sporadic cases are unifolcal.

Histology:
unencapsulated.
Focal calcifications are present.
Characteristic depostion of amyloid is seen in the tumour. <- A unique features in thyroid malignancy.
C cell hyperplasia is unique to familial cases.

Treatment:
Lymph node metastasis is common.
Total thyroidectomy with lymph node clearance is done.
Prophylactic thyroidectomy is done in children diganosed with MEN2 syndromes.

FMTC syndromes:

1. MEN2A - pheochromocytoma, hyperparathyroidism.
2. MEN2B - MTC, phaechromocytoma, marfanoid habitus and galngioneuromatosis.
3. FMTC - only MTC.

In treatment of MEN, to avoid intra op hypertension, resection of pheochromocytoma should be done before MTC resection.

[!TIP] Mnemonic for MEN syndromes
පා පා පි
පා මේ ෆි
මා මේ ෆි

Anapalstic thyroid CA

[!WARNING] A very, very bad cancer!
It is rare but has the worst prognosis of all thyroid CAs.
Occurs in older adults (60-70) -> older adult with a thyroid nodule could have a dangerous thyroid CA.
1 year survival is a dismal 20%. Median survival is 5-6 months.

Anaplastic CA grows rapidly. Many patients present with local invasion (unresectable tumours) or cervial lymph node metastasis.

On histology, the tumour retains feature so epithelial cells (presence of desmosomes) but there are large areas of necrosis and bleeding. There is high mitotic activity.

Bone tumours

• In adults, bone mets are far more common than primary bone tumours.

• Bone is the 3rd commonest site of metastatis next to Lung and liver.

• Prostate and breast cancer (BC) are responsible for the majority of the skeletal metastases (up to 70%).

• Other sources of bone mets : thyroid, renal cell carcinoma, lung cancer, melanoma

Bone metastasis

Bone mets are commonest in spine, pelvis and thigh.

Osteolytic :

1. Multiple myeloma
2. RCC
3. melanoma
4. NSCLC
5. Non Hodgkin Lymphoma
6. thyroid cancer
7. Breast cancer

Osteoblastic:

1. prostate cancer,
2. carcinoid,
3. small cell lung cancer,
4. Hodgkin lymphoma
5. medulloblastoma.

Ignore breast in this list!

Regarding prostate CA:
Pathologic fractures do occur, although they are generally less frequent than in cancers with predominantly osteolytic disease
Source

Multiple myeloma – The classic bone lesions in multiple myeloma are purely osteolytic due to increased bone destruction and suppressed bone formation.

Prostate cancer – Males with bone metastases from prostate cancer predominantly have osteoblastic (aka sclerotic) lesions with increased numbers of irregular bone trabeculae. Simultaneously, osteoclastic action is also increased.

Breast cancer - The great majority of breast CA produces osteolytic bone lesions, osteoblastic areas are also usually present

Renal cancer also commonly spreads to bone.

Atherosclerosis

#2022BSQ Q8
Plaques are raised lesions in the blood vessel.
Filled with cholesterol and cholesterol esters.

Overview of atherosclerosis

Atherosclerosis requires two factors

1. Endothelial dysfunction
   1. Involving altered gene expression (eg. incr. adhesion molecules) and increased permeability of endothelial cells.
   2. This allows migration of blood monocytes into the intima where they become macrophages.
2. Increased lipids in the blood
   1. Cholesterol and it's esters are found inside plaques. They stimulate chronic inflammation in the intim in the presence of macrophages.

Anything that exacerbates these two factors will promote atherogenesis.

1. Endothelial damage and dysfunction
   1. Smoking, hypertension, flow turbulence, some infection, ?toxins and drugs
2. Hyperlipidaemia
   1. Any condition increases blood lipid levels ?Which lipids exactly - not HDL.

In the presence of lipids within the intima, macrophages become activated. When they engulf lipids, they become foam cells.
Cytokines secreted by macrophages stimulate altered function and growth of smooth muscle cells of the media.
Smooth muscle cells proliferate and take on fibroblastic roles.
Smooth muscles + collagen produced by them form the fibrous cap of the plaque.

Plaques can

1. obstruct vessels
2. rupture -> thrombosis
3. weaken the media -> aneurysms

Factors which make a plaque unstable:

1. Thin fibrous cap
2. Increased foam cells
3. Increased lipid content etc.

Pancreatic physiology

#2022BSQ Q24

Secretin and CCK are endocrine hormones.
Secretin - role is to neutralize stomach effluent

• peptide hormone
• produced by S cells of duodenum and brain
• inhibits gastrin release -> to reduce stomach acid production
• Stimulates pancreatic secretion of fluid and bicarbonate
  Cholecystokinin - promote pancreatic enzyme secretion, and gall bladder contraction.

Secretin stimulation test: Although secreting physiologically inhibits gastrin secretion, in the presence of a gastrinoma, secretin paradoxically increases gastrin secretion. This is the basis of the secretin stimulation test for gastrinoma.

Selected gastrointestinal regulatory peptides

#2022BSQ Q24

See table 32.4 K and C.
Secretin glucagon family
Vasoactive intestinal peptide (VIP) -> Secreted by enteric NERVES -> Neurotransmitter, Stimulates insulin release, splanchnic vasolidation and intestinal secretion of water and electrolytes; also relaxes smooth muscles, including the lower esophageal sphincter and colon

Glucose dependent insulinotropic polypeptide - GIP - - From duodenum, gastric antrum and ileum - stimulated by intraduodenal glucose -> incretin effect. (produced by K cells)

GLP-1 - The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, to limit postprandial glucose rise. Secreted by L cells in the ileum and colon.

Humans have almost no L cells proximal to the ligament of treitz (i.e in the duodenum) Source

Secretion is likely triggered by glucose in the duodenum as well as the rest of the gut as well. Source

GLP-1 physiology

Source
Only a small percentage of the produced GLP-1 reaches the liver and systemic circulation because of the action of DPP-IV.

[!TIP] All of these hormones generally cause changes which promote digestion and absorption except for somatostatin

Bilirubin physiology and elevations

CT

[!INFO] Significance of active conjugated bilirubin secretion from hepatocytes
The active secretion of cojugated bilirugin into bile cannaliculi is rate limiting. But uptake of unconjugated bilirubin is very efficient.
Therefore, hepatocytes near the supplying veins will take up all the unconjugated bilirubin but may not be able to excrete all of it into the bile. Therefore, they reexcrete it into the sinusoids so that down stream hepatocytes can reuptake this conjugated bilirubin and help to excrete it into the bile canalliculi.
I.e more hepatocytes are recruited for excretion.
The transport proteins requried for reabsorption are affected in Rotor syndrome -> leads to conjugated and unconjugated hyperbilirubinaemia.

Complement system overview

Source

[!INFO] Functions of complement

• Promote inflammation through C3a, C4a and C5a
• Recruit cells (through chemoatractants)
• Kill targeted cells (bacteria)
• Solubility antigen-antibody complexes and remove them from circulation

The alternative pathway of complement activation depends on spontaneous hydrolysis of C3 in plasma leading to the formation of C3 (H2O). This molecule binds to factor B. Subsequent activation by factor D results in the formation of C3 (H2O) Bb. This complex cleaves additional C3 to C3a and C3b constantly and at a low rate. In the presence of an activating surface (e.g. a bacterial wall), C3b is protected from inactivation by regulatory proteins like factor I and H. As a result the more active alternative pathway C3 convertase C3bBb is formed, which is further stabilized by properdin.Source

Causes of increased CPK

#2022BSQ Q31
CPK = CK.
Creatine Kinase is a catalyst for the formation of ATP from ADP via transfer of phosphate from creatine phosphate (which is an energy reservoir for muscle.
It is a very good indicator of muscle breakdown and it's progression.
CPK is eleminated by the Reticuloendothelial system. Serum level isn't elevated in kidney disease.

3 isoforms

• Skeletal muscle - 99% CK MM

• CK-MB = Usually in cardiac muscle. Can also be elevated in elite athletes and normal people after strenuous exercise (i.e can produce false +ve for MI)

• CK is usually elevated in myopathies. => there are different types of myopathies

  • Inflammatory myopathies - polymyositis / dermatomyositis
  • Drugs - colchicine (gout), antimalarials, statins, alcohol
  • Metabolic myopathies - carnitine palmitoyltransferase deficiency, Muscle phosphorylase deficiency (McArdle's disease)
    • McArdles disease - Autosomal recessive, exercise intolerance in childhood followed by cramps and myoglobinuria
  • Endocrine myopathies - hypothyroidism, acromegaly
  • Periodic paralyses - hours to days of muscle weakness with sharp rises of CPK; due to muscle membrane refractoriness secondary to ion shifts.
  • Neuroleptic malignant syndrome
  • Malignant hyperthermia - usually follows use of anaesthetic agents.

• Can also be elevated in a few non myopathic conditions

  • Exercise
  • Iatrogenic muscle injury
  • motor neuron disease
  • Asymptomatic elevation in CK

Urine cultures

We went to get urine samples which contain bacteria which have managed to enter the bladder. (bacteria colonize the distal urethra and genital mucosa)
Theoretical best sample is first voided urine of the day as bacteria have had time to multiply overnight and it is also the most concentrated sample.
Suprapubic taps should yield sterile urine in a healthy patient.

Prostatic massage should be done prior to urine sample correction in suspected if chronic bacterial prostatis is suspected. Massage should be avoided in acute bacterial prostatits -> risk of bactiraemia!

Sample is cooled until it is send to the lab to prevent bacterial multiplication affecting the colony count.

Urine microscopye

pyuria

8 cells / microL = 2-5 cells per High power Field.
Very high associated with urinary infection.

• bacteuria without pyuria -> usually means colonization rather than infection. (unless of course, patient is symptomatic)

White blood cell casts - renal infection = could be pyelonephritis.

Causes of sterile pyuria:

• False -ve for bacteria
  • Contamination with antiseptic
  • Atypical pathogens - Chlamydia, Ureaplasma urealyticum, or tuberculosis
• False +ve for leukocytes
  • Contamination with vaginal leukocytes
  • Chronic intersitial nephritis - omeprazole is a cause.
  • Nephrolithiasis
  • Uroepithial tumour
  • Intrabdominal inflammation adjacent to the bladder

Cardiac action potentials

Source: CVS physiology website.

Electrolyte effects on ECG

Hyperkalemia
EKG changes progress from peaked T-waves to widened QRS and eventually to ventricular tachycardia, fibrillation or pulseless electrical activity arrest.  These progressive changes can correlate with rising potassium levels. For example, peaked T waves might correspond with a potassium level of approximately 6 mmol/L, whereas cardiac arrest generally occurs at higher levels.

Hypokalemia
EKG changes can include increased amplitude and width of P wave, T wave flattening and inversion, prominent U waves and apparent long QT intervals due to merging of the T and U wave and 'mild' ST depression.
The U-wave is a deflection following the T wave. . Potassium levels that are critically low (<1.7 mmol/L) can lead to torsades de pointes or“twisting of the points”, a polymorphic ventricular tachycardia.

[!INFO] U wave

• mechanism of generation isn't clearly identified
• normal u wave is concordant with the t wave
• it is smaller than the t wave (1/3 size)
• it's size increases with decreasing hear rate

Hypercalcaemia
The most common EKG finding associated with hypercalcemia is shortening of the QT interval. In severe cases, Osborn or J waves might be seen or ventricular fibrillation might ensue. Recognition of these EKG findings can prompt urgent treatment.

Hypocalcemia
The most common finding on EKG in patients with hypocalcemia is a prolonged QT interval.

https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.105.166563

doi.org/10.1016/0002-9149(63)90255-8

Hypermagnesaemia

Tumour markers

#2021BSQ-JUL Q31

[!TIP] GPT answer:
Certainly! Here is a list of common tumor markers and the tumors they are commonly associated with:

1. Prostate-Specific Antigen (PSA) - Prostate cancer
2. Carcinoembryonic Antigen (CEA) - Colorectal cancer, pancreatic cancer, lung cancer
3. Alpha-fetoprotein (AFP) - Liver cancer, germ cell tumors, particularly testicular cancer
4. CA-125 - Ovarian cancer
5. CA 19-9 - Pancreatic cancer, colorectal cancer
6. CA 15-3 - Breast cancer
7. CA 27-29 - Breast cancer
8. Human Chorionic Gonadotropin (hCG) - Germ cell tumors, particularly testicular cancer, ovarian cancer, ?lung CA
9. Calcitonin - Medullary thyroid cancer
10. Thyroglobulin - Thyroid cancer (papillary and follicular)
11. Neuron-Specific Enolase (NSE) - Neuroendocrine tumors, small cell lung cancer
12. Chromogranin A - Neuroendocrine tumors
13. S-100 Protein - Melanoma, neuroendocrine tumors
14. Human Epidermal Growth Factor Receptor 2 (HER2) - Breast cancer, gastric cancer
15. Epidermal Growth Factor Receptor (EGFR) - Non-small cell lung cancer, colorectal cancer
16. 5 HIA - carcinoid tumour
17. Carcinoid tumors are of neuroendocrine origin and derived from primitive stem cells in the gut wall, especially the appendix.

BRCA1 and BRCA2 - breast and ovarian cancer.

Inflammatory bowel disease

[!TIP] A great summary!
Source

[!INFO] Differentiation of disease is vital to determine the potential effectiveness of surgery!
resection is curative in UC but disease recurs after resection in Crohn's

Peak incidence for both is between 15-30 years. Buy disease can occur at any age.

[!INFO] 'Positive features' of Ulcerative colitis not seen in Crohn's disease

• Toxic megacolon can occur.
• Marked pseudopolyps
• ? More malignant potential
• Rectal involvement is always present
• primary sclerosing cholangitis (seen mostly with UC)

Extraintestinal manifestations of Crohn's disease

1. Migratory arthitis - appendicular skeleton. Parallels intestinal disease. Treatment of intestinal disease resolves arthritis.
2. Perichonlangitis - seen on ERCP or MRCP.
3. Kidney stones
4. Bowel inflammation -> ureteric obstruction and hydronephrosis
5. Fistulas

Ileal resection can cause bile acid malabsorption -> diarrhoea.****

Primary sclerosing cholangitis

• Progressive and chronic liver disease caused by autoimmune mediated fibrosis of intra and extrahepatic bile ducts.
• Strongly associated with IBD (mainly ulcerative colitis)
• Associated with pANCA positivity.
• Often complicated by recurrent cholangitis and cholangiocarcinoma.
• Treament is not curative; it's aimed at minimizing symptoms and managing complications.
• Liver transplantation is the only treatment than can alter progression. Drugs won't work.
• Affects young to middle aged males (in their 40s)
  • PSC without IBD is more likely to occur in women.
  • PSC is seen predominantly in non smokers.
  • (Remember that smoking protects against ulcerative colitis! so if you smoke, you have less risk of UC and associated PSC)
• Ix: AST, ALT, GGT all elevated. Fluctuating conjugated hyperbilirubinaemia.
• hypergammaglobulinaemia is present.
• Best imaging modality: MRCP
• ultimately leads to cirrhocis.

Primary Biliary Cirrhocis / Primary Biliary Cholangitis

[!TIP] PBC - the C can stand for Cirrhocis or Cholangitis.

[!TIP] When to suspect
Suspect in a middle aged woman with pruritus who has elevated ALP and possible other autoimmune conditions.

[!TIP] Mnemonic: Don't confuse with PSC - PBC has 'cirrhocis' in the name -> live tissue is inolved -> interlobular bile ducts are involved.

MCQ Discussion:
Most often diagnosed through routine screening. Usually asymptomatic.
But Fatigue is a prominent presenting symptom. Icterus and pruritus are late signs.

• 95% of PBC occurs in women aged 40 - 50 years.

• There is destruction of small interlobular bile ducts.

• Antimitochondrial antibodies are found in all patients. M2 is specific for PBC.

  • The presence of serum antimitochondrial antibodies (AMA) is a highly specific indication of primary biliary cirrhosis (PBC).

• Presentation: Asymptomatic with #hepatomegaly and raised ALP. (raised ALP is often the only abnormal investigation)

• Pruritus and fatigue.

• Raised cholesterol and Xanthelasma

• Associated with many autoimmune conditions.

• Histology: portal tract infiltrate with hepatic granulomas; changes start in zone 1.

• 

Immunoglobulin / antibody classes

#2022BSQ BSQ Q49

Types of immunoglobulins and antibodies
IgG IgA IgD IgM IgE

Source

Insulin

#2022BSQ Q40

Sources of insulin

Animal based : not commonly used.
Bovine insulin differs from human by 3 amino acids, porcine by 1 amino acid.

Pharmacokinetics

Regular insulin and NPH insulin are considered older insulins.
Their time to peak and duration of action don't mimic physiologic secretion.

(U-100) denotes the usual concentration (100 U/ml).

Regular insulin

Duration: Short acting.
Controls post prandial glucose rise.
Same AA sequence as human insulin.
Bound to Zinc.
Hexamers must be converted to dimers and monomer before absorption -> leads to a delay in peak concentrations-> should be given 30 minuted before meals.
Duration of action tends to exceede duration of post prandial glucose rise -> risk of hypoglycaemia.

NPH insulin

Duration: Intermediate.
Suspension of human insulin, protamine and zinc. -> delays release of insulin into blood, also longer time to peak.
Patient must eat after the morning dose is given, to avoid hypoglycaemia.

Delivery :

mix immediately before injection and given at room temperature.
NPH insulin is a cloudy solution.
Can be mixed with regular or rapid acting insulins in the syringe.
Always draw up the regular(clear) insulin first to avoid contaminating the regular insulin with isophane insulin, thereby altering its pharmacokinetics.

U-500 insulin

Not regularly used nowadays, partly because of the advent of DPP-4 inhibitors.

Insulin analogs

made by recombinant DNA technology.
Subsitution of amino acids produces rapid acting and long acting analogs.

Rapid acting insulins

Lispro, aspart, glulisine (and faster aspart, lipro-aabc)
Duration: (very short) duration and rapid onset

modifications were made in the insulin molecule to prevent it from forming hexamers or polymers that slow absorption and delay action

Insulin aspart- substitution of aspartic acid for proline at position B28.

Insulin lispro is identical to human regular insulin except for a lysine and proline at positions B28 and B29.

Insulin glulisine has a lysine and glutamic acid at positions B3 and B29 respectively.

Rapid acting insulins are move convenient.
U-200 lispro and U-200 lispro-aabc, are high concentration preparations which have some niche use cases.

Basal insulin analogs

Determir

Insulin detemir – Detemir is an acylated insulin; the fatty acid side chain allows reversible albumin binding as well as concentration-dependent self-association (ie, formation of dihexamers) that results in prolongation of action.
Determir is much less potent - so it is formulated in a 4:1 ratio. (1 Unit of determir contains four times as many insulin molecules as any other preparation of insulin)
Can't mix with rapid acting insulins.

Glargine

Glargine is identical to human insulin except for a substitution of glycine for asparagine in position A21 and by the addition of two arginine molecules to the amino terminus.

After subcutaneous administration, glargine precipitates in the tissue, forming hexamers, which delays absorption and prolongs duration of action.

Glargine, which is in an acidic solution, cannot be mixed with rapid-acting insulins, as the kinetics of both the glargine and rapid-acting insulin will be altered

Glargine has less nocturnal hypoglycemia than NPH insulin

Duration of action : 24 hours but some may need twice daily dosing as half life is 12 hours. Unlike glargine, it has a small peak in it's concentration profile.

Higher concentration preparations of glargine (U-300) have an even flatter concentration curve with lower hypoglycaemic effect.

Degludec

form multimers from which monomers are release-> even longer duration of action.
Can mix with rapid acting insulins.

Determinants of insulin efficacy

• Site of injection - Limbs are faster than abdomen. (muscle-> increased blood flow)

  • 

  NPH insulin - leg or buttock preferred for moderate rate of absorption.
  Pre meal regular insulin - abdominal wall preferred for rapid absorption.

The absorption of the long-acting basal insulin analogs, glargine and degludec, do not appear to be significantly influenced by injection site

• Technique
  • Too shallow: intradermal injection that is not well absorbed.
  • Too deep: intramuscular -> rapid absorption
  • 4mm neele - can give perpendicular injection
  • 6mm needle - give at 45 degrees.
  • Rotate sites to avoid lipohypertrophy.
  • Injection through clothes won't cause dlivery problems but it means that skin cannot be inspected before injection -> not recommended.
• Size of the depot
  • Larger depot size - less overall absorption and more variability in absorption.
• subcutaneous blood flow
  • reduced by smoking
  • Increased by exercise and hot baths.
  • Variations not as significant with long acting insulins.

Types of hypersensitivity

#2022BSQ Q48
#2022BSQ-MAY Q46

Hypersensitivity reactions refer to undesirable responses produced by the normal immune system - Source

[!INFO] Mnemonic
Type III - 3rd letter in alphabet - C for immune complexes.
[[Toxicology#Serum sickness]]

Type 5 hypersensitivity

Is when the produced antibodies have the property of stimulating receptors on cells. Best example is Grave's disease.
Source

[!TIP] Hypersensitivity Vs Autoimmune disease
Hypersensitivity is an abnormal immune response to a harmless stimulus. When the 'stimulus' is a self antigen, we call it autoimmunity.

Autoimmune diseases can be classified in the same way as hypersensitivity conditions. but IgE is not involved in autoimmunity.
so in the table[[2022 November SBR]] below, there is no "type I" in the autoimmune categories

Autoimmune diseases examples

Autoimmune diseases caused by antigens against cell surface receptors: [[moreAutoimmuneDiseases.png]]

Infectious diarrhoea

#2022BSQ Q54

Diarrhoea in resource rich settings

• can be studied under inflammatory diarrhoeal causes and watery diarrhoeal causes.
  See mnemonics below:

[!INFO] A Great table!
[[diarrhoeaInResourceRichSettings.png]] <- A great table!

[!TIP] Watery diarrhoea
"Noninflammatory diarrhea is caused by the action of enterotoxins on the secretory mechanisms of the mucosa of the small intestine, without invasion" - Medscape.

Same day:

1. Norovirus
2. clostridium perfringens
3. possibly listeria (pregnancy, immunosuppression, extremes of age)

Next day:

1. E coli - enteroroxigenic
2. most other viruses - (1-3 days) diarrhoea in children, immunocompromised adults

Same week

1. Cyclospora

Weeks later

1. Giardia 1 to 2 weeks later - day care, swimming pools, travel / camping.
2. Cryptosporidium 2-28 days (upto 1 month after) - Associated with day care centers, swimming pools.

^5eaea3

[!TIP] Mnemonics: inflammatory diarrhoea
Fever, mucoid or bloody stools show infective diarrhoea:
"Can't Assume Everyone's Your Very Special Sidekick"

Let's break it down:

1. "Can't" - Campylobacter
2. "Assume" - Amoebiasis
3. "Everyone's" - E. coli
4. "Your" - Yersinia
5. "Very" - Vibrio parahaemolyticus
6. "Special" - Salmonella
7. "Sidekick" - Shigella

Most of these have P-incu of 1-3 days. But, entamoeba - much longer- 1 to 3 weeks, yersinia - slightly longer- 4-6 days, E-coli 1-8 days.

Diarrhoea in resource poor settings

Epidemic diarrhoea

Main two pathogens of epidemic diarrhoea

1. Cholera (secretory rice water diarrhoea) [[Misc infectious diseases#Cholera]]
2. Shigella dysenteriae (bloody diarrhoea) - SD1 serotype. (inflammatory diarrhoea - blood + mucous)

Non epidemic diarrhoea

Commonest causes of non epidemic watery diarrhoea - E. coli.

[!TIP] mnemonic
Acute bloody diarrhoea
$$
\Large{C^1S^2E^3}
$$

Commonest cause of non epidemic bloody diarrhoea - shigella flexneri (not dysenteriae)

• other causes of acute bloody diarrhoea
  • Campylobacter
  • Enteroinvasive E coli
  • Enterhemorrhagic E coli
  • Entamoeba histolytica
  • [[Misc infectious diseases#Schistosoma|Schistosoma mansoni]]

Diarrhoea due to preformed toxins

#2021BSQ-NOV Q37

Symptoms suggesting diarhoeal illness caused by preformed toxins:

• Absolutely Rapid onset of symptoms : within hours.
  • Bacteria which start to form toxin after ingestion take time to produce symptoms. (usually> 24 hours)
• Vomiting predominates in the clinical picture.
• Pathogens causing diarrhoea this way are
  • Staphylococcus aureas - Toxin is produced on food at room temperature; food doesn't taste or smell odd. Onset as rapid as Source 30 minutes!
  • and Bacillsu cereus

Enterobiasis

Pin worm.
Humans are considered the only host for E. vermicularis
Infection is commonest in children and institutionalised people.
Treatment is easy; reinfection is also easy.
Commonest symptom: itching in the perianal area, possible with excoriation and seconday bacterial infection.
Perianal itching / scratching contributes to faeco-oral transmission of the parasite.
Infection of the female genital tract can occur. Can cause abdominal pain mimicking appendicitis.
Treatment: Albendazole, mebendazole

Strongyloidosis

Strongyloides stercoralis : thread worm
First discovered in french troops returning from vietnam in the 19th century who developed chronic diarrhoea.
Infective stage : Filariform larva: -> penetrates intact skin.

[!INFO] How to understand the life cycle;
parasite has a free living cycle and parasitic cycle
Eggs can be deposited a) In the host intestine and b) in the environment.
Eggs always produce rhabditiform larvae.
Eggs -> rhabditiform larvae -> filariform larvae. (Infective stage) (autoinfection or otherwise).
If excreted with stool, rahbditiform larvae can go on to develop into adult sexual stages which produce more eggs in the free living cycle.

Female Adult worm (who live embedded in the submucosa of the small intestine) lays eggs.

It has been thought that the L3 larvae migrate via the bloodstream and lymphatics to the lungs, where they are eventually coughed up and swallowed. However, L3 larvae appear capable of migrating to the intestine via alternate routes (e.g. through abdominal viscera or connective tissue)

Symptoms:

Respiratory : Dry cough - about 1 week after infection
Abdominal pain, bloating, intermittent constipation and diarrhoea - about 3 weeks or later after infeciton (due to infection of the small intestine)
Skin: Itchy rash at site of entry; recurrent red rash along thighs and buttocks. - Larva currens (pathognomonic of Strongyloidiasis).
Disseminated life threatening infection can occur in immunosuppressed people.
Eosinophilia(+)

Management:

Ivermectin has been shown to be superior to albendazole.

Ivermectin: binds selectively and with high affinity to glutamate-gated chloride ion channels in invertebrate muscle and nerve cells of microfilaria.

Albendazole and other similar drugs inhibit the beta tubulin of worms (intracellular cytoplasmic structural protein) -> immobilization and death.

Skull base fracture

#2022BSQ Q51
Skull base fracture and associated injuries; Source
NCBI article <- good link
Cranial nerve injuries: Page 1079 of Moore's clinical anatomy.

Sjogren syndrome

#2022GM Q14
#2021GM-JUL/Q17

Pathogenesis: Autoimmune disease affecting exocrine glands.

In most cases, Sjogren syndrome is only 'irritating' and not dangerous.

Can occur as a primary disorder or secondary to another rheumatic disease.

Symptoms are classified mainly as

1. Exocrine gland symptoms
   1. Predominant symptoms of Sjogren's syndrome are
      1. oral dryness (affects salivary glands)
      2. and dry eyes. - assessed by Schirmer test < 5mm/min. (filter paper used to assess tear production)
2. Extra glandular symptoms
   1. Skin :
      1. Xerosis (dryness)
      2. Raynaud's phenomenon
      3. Cutaneous vasculitis: Palpable purpura is the commonest manifestation.
   2. Muskuloskelatal: Arthralgria, myopathy, fibromyalgia.
   3. Associated with autoimmune thyroiditis.
   4. Lungs - interstitial lung disease; upper and small airway involvement; Patients have cough and dyspnoea.
   5. Peripheral neuropathy
   6. Depression / mood changes/ mild cognitive impairment (maybe due to poor sleep)
   7. Mild anaemia and leukopenia
   8. Other autoimmine diseases
      1. Myasthenia gravis
      2. Autoimmune hepatitis/ pancreatitis.
   9. Increased incidence of Non Hogdkins B lymphoma.
   10. Can cause renal involvement - hypokalemia is common secondary to distal renal tubular acidosis[[2021-SBR-November#Renal tubular acidosis]] with K+ wasting.
   11. Rare complication of Sjogren syndrome during pregnancy : congenital heart block.
   12. ?Dysphagia with abnormal oesophageal motility.

Spectrum of disease:

Mild disease : just dry eyes and mouth; Requires diagnostic criteria to be fullfilled to diagnose SjD.

Severe disease:
A severely affected patient may have florid salivary gland enlargement, adenopathy, antibodies to the Ro/SSA and La/SSB antigens, cryoglobulinemia, hypocomplementemia, a propensity to develop non-Hodgkin lymphoma, and other extraglandular disease manifestations.

90% are positive for Rheumatoid factors: Kumar and Clark

Epidemiology: Most Commonly occurs in women aged 50-60 years old.

Associated conditions

Keratoconjuntivis sicca - term for the occular manifestations of Sojgrens.
Mikulicz syndrome: Parotid and lacrimal gland enlargement; Sojgren's disease is one possible cause of this.

Diagnostic criteria:

Biopsy showing focal lymphocytic infitrate of labial salivary glands. Termed Focal lymphocytic sialadenitis.
Objective test: Focal lymphocytic sialadenitis score >= 1;

Anti Ro/SSA and anti La / SSB positivity suggests Sojgren's disease.

Background of systemic autoimmune disease. -
The most common associations are SLE and Rheumatoid arthritis.

Pathogenesis of ascites in Cirrhocis

Several haemodyanic and vascular changes occur which contribute to the formation of cirrhocis.

Vascular:

• Decreased peripheral resistance (and reduced arterial pressure)
  • (most apparent in the splanchnic circulation)
• Increased circulatory volume
• Increased cardiac output (and tachycardia)
• Increased portal blood flow
• I.e Hyperdynamic circulation is present.
  but, with
• Decreased renal perfusion (kidneys compensate by increasing their production of prostacyclin - a vasodilator. This effect is lost in patients with hepatorenal syndrome and can be inhibited iatrogenically by NSAIDS -> both causing a ==disastrous== fall in renal plasma flow!)

Multiple mediators have been studied as sources of the systemic vasolidation but the most important one seems to be increased NO synthesis.

inhibition of synthesis of NO in rats restores normal arterial pressure.

? cause for increased NO
Portal hypertension -> increased portosystemic shunting -> decreased hepatic clearance of bacterial toxins / DNA absorbed from GI tract.

mediated by vascular changes:
Splanchnic vasodilation
Renal artery vasoconstriction
(and also pulmonary vasodilation)

Ascites: The pathological accumulation of fluid in the peritoneum.
Development of portal hypertension is the first step and is essential for the formation of ascites in cirrhocis.

Older theories of ascities formation : undefill theory and overflow theory. Modern arterial vasodilation hypothesis fits better with data.

Arterial vasodilation theory of ascites formation

A portal pressure >12 mmHg appears to be required for fluid retention
Portal hypertension is not simply due to mechanical obstruction of the portal system. It occurs due to increased flow from the splanchnic arteries.

See hypothesis-highlights on UpToDate

SAAG

#2022GM Q32
Serum 'to' Ascites Albumin gradient

SAAG > 11g/L - low protein in ascitic fluid => Suggest portal hypertension as cause; (i.e transudate)
SAAG < 11g/L - high protein in ascitic fluid (or low serum protein) => Exudate (?malignancy)

Low ascitic fluid protein may increase the risk of SBP as there are no opsonins in the fluid to combat infection.

Liver transplantation

Indications for liver transplantation

1. Acute liver failure of any cause
2. Chronic hepatic failure with Childs grade > C or MELD > 20;
   1. hepatopulmonary syndrome can be reversed by hepatic transplantation.
3. Primary biliary cholangitis
4. Chronic hepatitis B is HBV DNA negative or falling; recurrence of infection is prevented by HBIG and nucleoside analogues.
5. Autoimmune hepatitis
6. Alcoholic
7. Metabolic disorders - haemochromatosis, Wilsons, Alaph a antitrypsin deficiency
8. NASH cirrhocis

Bronchiectasis

#2022GM Q21

Review of airway histology

Respiratory epithelium - ciliated pseudostratified columnar epithelium.

Note the presence of smooth muscle and it's decreasing thickness as the airways become smaller.

Bronchioles - intralobular airways < 1mm in diameter arising roughly after the 10th generation of branching.

Epidemiology

Commoner in women.
Increases with age; marked increase after 60 years.

Pathology

Bronchiectasis is the permanent dilation of bronchi and
bronchioles caused by destruction of the muscle and the
supporting elastic tissue, resulting from or associated with
chronic necrotizing infections. It is not a primary disease
but rather secondary to persisting infection or obstruction
caused by a variety of conditions

Obstructive impairment (ie, reduced or normal FVC, low FEV1, and low FEV1/FVC) is the most frequent finding on spirometry. ;
$$
\LARGE{Obstruction = ↓\frac{FEV_{1}}{FVC}}
$$

See [[Lung function tests#Obstructive vs. restrictive diseases]]

Morphology

Usually affects bilateral lower lobes.
Permanent dilation -> small airways are traceable almost upto the pleura. (in normal lungs, they stop about 2 cm short of the pleura)
Chronic inflammatory exudate is seen.
Extensive desquamation of epithelium causing ulceration.
Healing is usually by fibrosis.
Abscesses can form as complications.

Diagnosis:

Clinical and CT:
CT features that are reliable signs of bronchiectasis:

• Airway-to-arterial ratio ≥1.5 (internal airway lumen diameter/adjacent pulmonary artery diameter)
• Lack of tapering of bronchi (tram track appearance)
• Airway visibility within 1 cm of a costal pleural surface or touching the mediastinal pleura

Causes of bronchiectasis and basis of disease

Common causes

Obstruction - tumour, lymph nodes, aspiration etc. <- impaired drainage
Inherited disorders -
Cystic fibrosis <- impaired clearance of mucous
Kartagener syndrome <- Ciliary impairement
Autosomal recessive #autosomal-Recessive
Situs inversus, chronic sinusitis, and bronchiectasis; Underlying pathology is primary ciliary diskinesia. Kartagener Xn is a subset of primary ciliary diskinesia (in which patients may not have situs inversus).
Screening test -> patients have low levels of nasal nitric oxide.

Immunoglobulin deficiencies <- recurrent infection
Necrotizing of suppurative pneumonia - staph aureus or klebsiella <- scarring and impaired clearance; ?exagerrated neutrophil response

Other causes

Young syndrome - similar to CF but no evidence of CF; rare diagnosis nowadays.
Associated with two rheumatic disorders - Sjogren syndrome and Rheumamtoid arthritis.
[[General Medicine 1#Allergic bronchopulmonary aspergillosis|Allergic bronchopulmonary aspergillosis]] - ? central bronchiectasis

Management

Antibiotics for exacerbations
Control of acute bleeding with bronchoscopic local therapy or bronchial artery embolization.
Refractory disease: surgical therapy - ? resection

Immunodeficiency syndromes

• Primary immunodeficiencies arise from inborn defects. They usually present in childhood.
  • Common variable immunodeficiency is a notable exception to this.
• Seconday immunodeficiency is far more common (?in adult populations)
  • Diabetes mellitus
  • Human immunodeficiency virus (HIV) infection
  • Cirrhosis
  • Nephrotic syndrome
  • Other protein-losing states, such as enteropathies, severe exudative skin disease including burn injury, and peritoneal dialysis
  • Malnutrition
  • Hemoglobinopathy
  • Inflammatory bowel disease or rheumatoid arthritis receiving immunosuppressive therapies (particularly tumor necrosis factor [TNF] inhibitors)
  • Neurologic disease
  • Autoimmune disease
  • Splenectomy
  • Malignancy
  • Radiation therapy
  • Immunosuppressive agents, such as glucocorticoids and others
  • Immunomodulatory agents, such as rituximab, etanercept, and others

Typical presentations and associated defects in the immune system

#2022BSQ-MAY Q49

Skin infections, in isolation, are not usually indicative of an underlying primary immunodeficiency.
Chronic mucocutaneous candidiasis - ussually begins in childhood; associated with several immunodeficiency states; usually doesn't show systemic infection with the fungus.
Recurrent herpevirus infection / reactivation -> These individuals should be evaluated for underlying T or natural killer (NK) cell dysfunction. See -> [[2021 Basic Sciences July#Natural killer cells]]
 ***
 However, recurrent respiratory tract infections in combination with more serious infections are a classic presentation of antibody deficiencies.
 ***
~~>  
 - Isolated urinary tract infections are more suggestive of anatomic defect than immunodeficiency.
 - Relapsing, recurrent, and/or progressive enterocolitis due to common enteropathogens, such as Giardia, enteroviruses, cytomegalovirus, and campylobacter, are associated with underlying hypogammaglobulinemia and/or T cell immunodeficiency.
 
 - Recurrent Neisseria meningitidis meningitis -> Deficiency of one or more of the terminal complement components (C5, C6, C7, C8, C9) . Low complement levels may be due to either congenital complement deficiency or acquired diseases, such as systemic lupus erythematosus.
 - Immunoglobulin deficiency disorders or impaired reticuloendothelial function resulting from splenectomy or hemoglobinopathy are associated with an increased risk of bacteremia and meningitis due to encapsulated pathogens.
 - Marked elevation of serum IgE with multisystem infections -> Job syndrome
~~

Immunoglobulin / antibody deficiencies

Usually due to defects in B lymphocytes -> not enough antibodies produced.

Recurrent sinopulmonary infections and persistence of gut pathogens.
Leads to bronchiectasis and chronic diarrhoea with malabsorption.

Common variable immunodeficiency

[!INFO] Commonest significant antibody deficiency affecting children and adults.

Diagnosed at: 20 and 45 years of age.

? etiology - few are inherited. Pattern may by #autosomalDominant with low penetrance or #autosomal-Recessive - UpToDate

There is

• B cells are present but they don't produce antibodies (i.e are ?nonfunctional?)
  • B cell numbers are normal but there are low levels of isotype switched B memory cells and plasma cells.
• Low levels of all immunoglobulin classes
• Frequent bacterial infections.

Lymphoma is a common cause of death in these patients.

Complications:

• Recurrent infections - sinopulmonary (with encapsulated Streptococcus pneumoniae and Haemophilus influenzae and others) -> can lead to bronchiectasis.
• Autoimmune disorders - RA, vitiligo, haemolytic anaemia.
• Lymphoma

Chronic giadia infections with malabsorption can occur.

Treatment is IVIG.

Selective IgA deficiency

Commonest primary immune deficiency.
Individuals are usually asymptomatic. -> treatment is only antibiotics as needed.
Can present with recurrent mucosal pyogenic infections.

Agammaglobulinaemia

#2021BSQ-JUL Q24
Also called hypogammaglobulinaemia.

Mutation of the BTK gene impairs B cell maturation -> causes low or absent mature B cells -> severe hypogammaglobulinaemia.
Commonest inheritance: #x-linked-recessive with mothers being carriers. #autosomal-Recessive inheritance is seen in ? 50%. - confirm

Manifestation: recurrent sinopulmonary infections.(From 6 to 12 months of age, otitis media, sinusitis, bronchitis, and pneumonia).
Common pathogens: Encapsulated pyogenic bacteria Haemophillus influenzae and strep pneumoniae.

Treatment: repeated IVIG transfusions or stem cell transplant.

Complement deficiency

[[2022-November#Complement system overview]]
Impaired alternative pathways -> non specific impairement -> bacterial infections.

Impaired classical pathway -> increased infection and increased immune complex deposition -> SLE, vasculitis, glomerulonephritis etc.

MAC -> neisseria infections.

Severe combined immunodeficiency - SCID

#2022BSQ-MAY Q49

• Commonest form is impaired #x-linked-recessive .

• Defect is in IL-2 receptor.

  • IL-2 is a cytokine which causes proliferation of T lymphocytes specific to a particular antigen. (Figure 4-4 Robbins)

• T and NK cells are lacking in the blood.

• Presentation is similar to pure T lymphocyte deficiency:

• That is, infections with fungi, protozoa, intracellular organisms.

• persistent and recurrent diarrhoea, otitis media, thrush, and respiratory infections

• Treated with Stem Cell transplant.
• Presents before 3 months of age; without treatment babies die before 2 years of age.

Immune response to fungi

[[ImmuneResponsesTofungalpathogens.pdf]]
Not as well understood as bacteria and viruses.
Pattern recognition receptors (PRR) on antigen presenting cells are triggered by fungal cell components.
This causes intracellular signalling of the APC which promotes phagocytosis and stimulates killing mechanisms.
The adaptive immunity to fungi is mediated by CD4+ Th1 cells with produce interferron gamma and CD4+ Th17 cells which produce IL-17. They drive killing by innate effector cells like marcophages and neutrophils.

So overall,

1. neutrophil defects cause systemic candiasis
2. T cell defects cause mucocutaneous candidiasis.

OPSI - overwhelming post splenectomy infection

Splenectomy leaves the patient vulnerable to infection by capsulated organisms.

1. Streptococcus pneumoniae
2. Haemophillus influenzae
3. Neisseria meningititis

More than half of those with OPSI die.

Why specifically encapsulated organisms?

Encapsulated organisms are resistant to phagocytosis without opsonization.
The spleen is a major site of early IgM production.

IgM memory B cells produce IgM to promote the clearance of polysaccharide-encapsulated bacteria.

Although the total B lymphocytes remain intact, a significant fall in the levels of memory B cells and switched B cell proportions are usually encountered 150 days post-splenectomy. This acts as a particular predisposition to infections caused by polysaccharide-encapsulated bacteria and is responsible for a diminished immunological response to polysaccharide vaccines
Source

However, even after opsonization, the bacteria must be phagocytosed. Splenic macrophages are a major contributor to this phagocytosis.
So in asplenia, there is impaired IgM production and thus opsonization and also impaired phagocytosis.

Amyloidosis

"Amyloid" was meant to describe the starch like properties of the substance. Initially described as "waxy" and "lardaceous".

Subtypes of amyloidosis

There are 18 different types of systemic and 22 localized forms of amyloidosis

The four most common causes of systemic amyloid deposition are

1. AL amyloidosis
2. ATTRwt - wild type transthyretin amyloidosis
3. Hereditary (famliliarl) amyloidosis
4. AA amyloidosis

[!INFO] AL Vs AA : importance of differentiating
AL amyloidosis must be differentiated from other forms of amyloidosis (eg, AA amyloidosis, ATTRmt amyloidosis, and ATTRwt amyloidosis) since the latter are non-neoplastic and will not benefit from chemotherapy.

Other forms of amyloidosis:

• Heritable amyloidosis types
• Organ specific amyloidosis
• Dialysis related amyloidosis

Diagnosis

Histological : Fat pad biopsy (less risk of bleeding)
Organ biopsy is needed if a specific organ is involved.

When congo red stains binds to amyloid protein, it produces apple green birefringence.

Looks similar to DM nephropathy but the staining characteristics are different (DM nephropathy is PAS and silver stain positive)

Cutaneous manifestations of amyloidosis

• purpura, petechiae, and ecchymoses following minor trauma ("pinch purpura")
• Appearance of periorbital purpura following a Valsalva maneuver or dependent positioning of the head. Macroglossia (picture 16), waxy papules and plaques, enlarged shoulder pads, bullous lesions, and sclerodermatous changes in the skin may also be seen. (UpToDate)

AL amyloidosis

AL amyloidosis is Associated with plasma cell dyscrasia (multiple myeloma, waldenstrom macroglobulinemia)

Symptoms and signs

There is multisystem amyloid deposition

• Fatigue, non intentional weight loss

• Heavy proteinuria (70%) - nephrotic syndrome

• oedema

• #hepatosplenomegaly (hepatomegaly +/- splenomegaly seen in 70%)

• Cardiomyopathy and heart failure (60%) - thickening of interventricular septum is present / MI due to accumulation of amyloid in coronaries.

  • Cardiomyopathy is common in AL and ATTR but rare in AA amyloidosis

• Neuropathies - carpal tunnel, mixed sensory and motor peripheral neuropathy is a prominent feature in AL amyloidosis. (Symptoms of numbness, paresthesia, and pain are frequent)

• Amyloid infiltration of muscles - macroglossia with scalloping and shoulder pad sign. (also enlarged deltoids)

• Skin - purpura (raccoon eyes with valsalva maneuver is specific), waxy skin, easy bruising.

• Coagulopathy - possibly due to factor X binding of coagulation factors to amyloid.

• GI involvement: gastroparesis, constipation, bacterial overgrowth, malabsorption, and intestinal pseudo-obstruction resulting from *dysmotility

  Criteria for organ involvement

Treatment

Bortezomi based induction
Melphalan
Haematopoietic cell transplantation.

Prognosis

This disorder has a poor long-term prognosis, with cardiac or hepatic failure, and infection being the major causes of death
Earlier detection confers better outcome.

AA amyloidosis

The most common organ affected by AA amyloid is the kidney (approximately 80 percent of patients -> causes nephrotic syndrome.

AA amyloidosis may complicate chronic diseases in which there is ongoing or recurring inflammation, such as rheumatoid arthritis (RA), spondyloarthritis, or inflammatory bowel disease; chronic infections.

Symptoms

SImilar to AL (but cardiomyopathy is rare)
GI involvement: similar to AA amyloidosis

Treatment

In untreated patients, AA (secondary) amyloidosis carries a significant risk of mortality due to end-stage kidney disease, infection, heart failure, bowel perforation, or gastrointestinal bleeding.
Successful treatment of the underlying inflammatory process improves kidney function.

Spondyloarthritis (SpA)

Spondylos = greek for vertebrae

common features

• chronic low back pain
• positivity for HLA B27 antigen (present in 90% of those with AS)
  • (However, there is high background positivity of approx 8% so HLA isn't usually used in diagnosis. )
• radiographic changes in the sacroiliac joints in patients with axial SpA
• and asymmetric (oligo)arthritis, heel enthesitis and dactylitis in patients with peripheral SpA
• uveitis, inflammatory bowel disease, psoriasis, and increased levels of acute phase reactants

Uveitis
The presence of leukocytes in the anterior chamber of the eye is characteristic of anterior uveitis.
The presence of leukocytes in the vitreous humor - intermediate uveitis
Evidence of active chorioretinal inflammation -> posterior uveitis

• Rheumatoid factors negative. (<- Seronegative arthropathies)

characteristic radiographic features

Sacroiliac joint:
sclerosis,
joint space widening, or erosion (fusion in late stages)
syndesmophytes and changes of spondylitis in the spine, which are most often detected in more longstanding disease.

A syndesmophyte is a bony growth originating inside a ligament, commonly seen in the ligaments of the spine, specifically the ligaments in the intervertebral joints leading to fusion of vertebrae.

Inflammatory osteoproliferative lesions in the spine are called syndesmophytes (marginal and non-marginal), and degenerative osteoproliferative lesions are called osteophytes. Syndesmophytes are more vertically oriented than osteophytes.

subtypes of SpA

• Ankylosing spondylitis
• Psoriatic arthritis
• Reactive arthritis
• IBD related arthritis
• And some other types
  • nonradiographic axial SpA (nr-axSpA), peripheral SpA,

#TODO add image of enthesis

Ankylosing spondylitis

#2022GM Q25
#2022GM Q27

Ankylosing = stiffness or fixation of a joint by disease

Affects teens to early 30s, male >> female (5:1).
Pathology: lymphocyte and plasma cell infiltration of the attachments of ligaments. (enthesitis)

Some terminology: not super important

Pathogenesis of AS

SourceGreat article!
HLA-B27

[!INFO] Key points

• It's largely a genetic disease - Patient's children have increased risk of getting it
• Pathogenesis consists of inflammation, bone erosion and syndesmophyte formation.
• Bone erosion and syndesmophyte formation are probably not linked to inflammation
• TNF-blockage suppresses symptoms but doesn't arrest bone changes.
  
  

Clinical features of AS

• Intermittent episodes of sacroiliac joint inflammation
  • Chronic back pain which is reduced by exercise.
• Uveitis and costochondritis suggest back pain of rheumatic origin (i.e AS)
• Peripheral Joint involvement is asymmetrical and involves the large joints.
  • (eg Hip)
  • ankles, hips, knees, shoulders, and the sternoclavicular joints
• Axial joints
  • Formation of syndesmophytes can lead to fusion of vertebrae. (Shobers test detects a stiff spine in early stages)
  • Advanced cases: fusion of the sacroiliac joints, and bamboo spine. (Gadolinum MRI is more sensitive than Xray at detecting early changes).
• Dactylitis - sausage shaped fingers and toes
• Extra-articular manifestations
  • Uveitis - can present as painful eye with photophobia and blurred vision -> emergency!
  • Aortitis

Management of Anky Spondi

• Prevention of syndesmophyte formation -> early diagnosis and initiation of exercise regimen.
• NSAIDS for pain relief to enable exercise during exacerbations.
• MTX -> good for peripheral arthritis but will not work for spinal disease. Only exercise👆
• TNF-α blockers - etanercept and adalimumab provide HUGE symptomatic relief. They reduced morbidity
• Children of affected person have a 30% change of developing anky Spondi.
• Overall prognosis is good with exercise and pain relief, allowing 80% of patients to remain employed.

Aplastic anaemia

#2022GM Q30
Congenital

• fanconi anaemia

• dyskeratosis congenita
• Familiar aplastic anaemia
• Cartillage hair hypoplasia
• Diamond-blackfan anaemia

Acquired

• infection - EBV, hepatitis, parvovirus, mycobacteria
• Ionizing radiation
• Benzene, pesticides
• GVHD
• Pregnancy
• anorexia, severe nutritional deficiencies
• PNH

Hepatosplenomegaly and lymphadenopathy are rare.